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Liquid Biopsy: The Cool Kid on the Block George M Yousef MD PhD FRCPC Division Head, Molecular Diagnostics Department of Laboratory Medicine St. Michael’s Hospital, Toronto, Canada Associate Professor, Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada [email protected]
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Liquid Biopsy The Cool Kid on the Block
George M YousefMD PhD FRCPC
Division Head Molecular Diagnostics
Department of Laboratory Medicine
St Michaelrsquos Hospital Toronto Canada
Associate Professor Department of Laboratory Medicine and Pathobiology
University of Toronto Canada
yousefgsmhca
Tissue Biopsy Tissue inaccessibility
Costly
invasive
Complications and side effects
Inadequate Sampling
10-50 failure rate
Liquid Biopsy Non-invasive
Cheaper
Can be repeated
Reduced morbidity
Chin J Cancer (2016) Apr 735(1)36Disease Markers (2015) Apr20151-9
Serum plasma
Saliva
Cerebrospinal fluid
Seminal Plasma
Urine
Clin Chem (2016) Jun 3Dis Markers (2015)2015251403J Proteomics (2014) Feb 269844-58
1 Cell-free DNAbull DNA fragmentsbull From necrotic or apoptotic cells
lymphocytesbull Found in urine serum plasmabull Multiple applicationsbull Short half life
2 Proteinspeptidesbull Quantitative global assessment
Label-free mass spectrometry
3 Circulating RNAs
miRNAs lncRNAs mRNAs
4 Circulating Tumour Cellsbull Shed from primary or metastatic lesions
bull Often low abundance
bull Very rare in healthy individuals
bull Require immediate processing
5 Exosomesbull Protects RNA (miRNA lncRNA) DNA
Proteins
Chin J Cancer (2016) Apr 735(1)36Translat Cancer Res (2015) 4 280ndash290
Technology breakthrough Next generation sequencing
ddPCR Unprecedented sensitivity
Multiple targets simultaneously
More parameters to assess
Improved collection Streck tubes (1 W room temperature)
Bioinformatics
Cancer Monitor treatmentsurgery success
Early detection of recurrence
Prognosis
Diagnosis
Prenatal screening
Transplantation rejection
Pharmacogenomics
Apoptotic cell
necrotic cell
Cell-free DNA
Can analyze
1 cfDNA levels2 cfDNA integrity 3 CpG island (promoter) methylation 4 Copy number variation5 Mutations
Sequencing
screening for CNA
screening for mutations
Murtaza Nature 2013
Schuumltz Clin Chem 2015
Droplet digital PCR (ddPCR)
targeted SNPs
Oxnard Clin Cancer Res 2014
Loacutepez Int J Mol Sci 2016
Thress Nature Medicine 2015
Gao J Thorac Oncol 2010
Quantitative allele-specific real-
time PCR (Idylla)
Janku Mol Cancer Ther 2016
Competitive allele-specific TaqMan
PCR (cast-PCR)
Ashida Int J Clin Oncol 2016
Co-amplification at lower
denaturation temperature (COLD)-
PCR
Freidin Clin Chem 2015
BEAMing assay Diehl PNAS 2005
cfDNA Technology platforms
McDermott U (2011) N Eng J Med 364(4)340-50
On the basis of a tumor-biopsy sample massively parallel paired-
end sequencing detects chromosomal rearrangements that can be used to monitor relapse or response to treatment from serial blood samples from the patient
Assessment of a limited number of chromosomal structural instabilities by use of massive parallel sequencing of cfDNA was sufficient to distinguish between prostate cancer and controls
Pantel et al (2010) Trends in Molecular Med
Technologies for Isolating CTC
BREAST CANCER (bone marrow and peripheral blood)
bull Reliable prognostic factor bull Presence of CTC after neo-adjuvant chemotherapy indicates a
high risk for relapse and deathbull Included in ASCO staging M0(i+)
COLORECTAL CANCERDetection of CTC in peripheral blood of patients with resectable colorectal liver metastases or widespread mCRC is associated with disease progression and poor survival
Clinical Utility of Circulating Tumor Cells
Predictive of progression-free survival and overall survival in patients with
biochemical failure
The change in the number of CTC correlates with disease progression
Yu et al (2011) J Cell Biol
bull HER-2 and ERPR status in CTC
bull EMT and stem cell markers
The US-Canada border
What are miRNAs
bull Single-stranded 20-23 nucleotide RNA fragments
bull Do not code for proteins
bull Post-transcriptional regulators
mRNA degradation Translational inhibition
ldquosmall RNAs with a big role in gene regulationrdquoHe L and Hannon GJ Nature reviews genetics 5522-531 2004
A signature that can reliably distinguish normal and cancer
New diagnostic markers
miRNA Dysregulation In ccRCC
White et al J Urol 2011
Chen et al Trends in Cell Biology 2012
Circulating miRNAs
Butz et al Eu Urol Focus in press
Non-invasive urine biomarkers
p= 0016
p= 0007
p= 0033
p= 0033
p= 0019p= 012
p= 0020
p= 0146
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Tissue Biopsy Tissue inaccessibility
Costly
invasive
Complications and side effects
Inadequate Sampling
10-50 failure rate
Liquid Biopsy Non-invasive
Cheaper
Can be repeated
Reduced morbidity
Chin J Cancer (2016) Apr 735(1)36Disease Markers (2015) Apr20151-9
Serum plasma
Saliva
Cerebrospinal fluid
Seminal Plasma
Urine
Clin Chem (2016) Jun 3Dis Markers (2015)2015251403J Proteomics (2014) Feb 269844-58
1 Cell-free DNAbull DNA fragmentsbull From necrotic or apoptotic cells
lymphocytesbull Found in urine serum plasmabull Multiple applicationsbull Short half life
2 Proteinspeptidesbull Quantitative global assessment
Label-free mass spectrometry
3 Circulating RNAs
miRNAs lncRNAs mRNAs
4 Circulating Tumour Cellsbull Shed from primary or metastatic lesions
bull Often low abundance
bull Very rare in healthy individuals
bull Require immediate processing
5 Exosomesbull Protects RNA (miRNA lncRNA) DNA
Proteins
Chin J Cancer (2016) Apr 735(1)36Translat Cancer Res (2015) 4 280ndash290
Technology breakthrough Next generation sequencing
ddPCR Unprecedented sensitivity
Multiple targets simultaneously
More parameters to assess
Improved collection Streck tubes (1 W room temperature)
Bioinformatics
Cancer Monitor treatmentsurgery success
Early detection of recurrence
Prognosis
Diagnosis
Prenatal screening
Transplantation rejection
Pharmacogenomics
Apoptotic cell
necrotic cell
Cell-free DNA
Can analyze
1 cfDNA levels2 cfDNA integrity 3 CpG island (promoter) methylation 4 Copy number variation5 Mutations
Sequencing
screening for CNA
screening for mutations
Murtaza Nature 2013
Schuumltz Clin Chem 2015
Droplet digital PCR (ddPCR)
targeted SNPs
Oxnard Clin Cancer Res 2014
Loacutepez Int J Mol Sci 2016
Thress Nature Medicine 2015
Gao J Thorac Oncol 2010
Quantitative allele-specific real-
time PCR (Idylla)
Janku Mol Cancer Ther 2016
Competitive allele-specific TaqMan
PCR (cast-PCR)
Ashida Int J Clin Oncol 2016
Co-amplification at lower
denaturation temperature (COLD)-
PCR
Freidin Clin Chem 2015
BEAMing assay Diehl PNAS 2005
cfDNA Technology platforms
McDermott U (2011) N Eng J Med 364(4)340-50
On the basis of a tumor-biopsy sample massively parallel paired-
end sequencing detects chromosomal rearrangements that can be used to monitor relapse or response to treatment from serial blood samples from the patient
Assessment of a limited number of chromosomal structural instabilities by use of massive parallel sequencing of cfDNA was sufficient to distinguish between prostate cancer and controls
Pantel et al (2010) Trends in Molecular Med
Technologies for Isolating CTC
BREAST CANCER (bone marrow and peripheral blood)
bull Reliable prognostic factor bull Presence of CTC after neo-adjuvant chemotherapy indicates a
high risk for relapse and deathbull Included in ASCO staging M0(i+)
COLORECTAL CANCERDetection of CTC in peripheral blood of patients with resectable colorectal liver metastases or widespread mCRC is associated with disease progression and poor survival
Clinical Utility of Circulating Tumor Cells
Predictive of progression-free survival and overall survival in patients with
biochemical failure
The change in the number of CTC correlates with disease progression
Yu et al (2011) J Cell Biol
bull HER-2 and ERPR status in CTC
bull EMT and stem cell markers
The US-Canada border
What are miRNAs
bull Single-stranded 20-23 nucleotide RNA fragments
bull Do not code for proteins
bull Post-transcriptional regulators
mRNA degradation Translational inhibition
ldquosmall RNAs with a big role in gene regulationrdquoHe L and Hannon GJ Nature reviews genetics 5522-531 2004
A signature that can reliably distinguish normal and cancer
New diagnostic markers
miRNA Dysregulation In ccRCC
White et al J Urol 2011
Chen et al Trends in Cell Biology 2012
Circulating miRNAs
Butz et al Eu Urol Focus in press
Non-invasive urine biomarkers
p= 0016
p= 0007
p= 0033
p= 0033
p= 0019p= 012
p= 0020
p= 0146
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Serum plasma
Saliva
Cerebrospinal fluid
Seminal Plasma
Urine
Clin Chem (2016) Jun 3Dis Markers (2015)2015251403J Proteomics (2014) Feb 269844-58
1 Cell-free DNAbull DNA fragmentsbull From necrotic or apoptotic cells
lymphocytesbull Found in urine serum plasmabull Multiple applicationsbull Short half life
2 Proteinspeptidesbull Quantitative global assessment
Label-free mass spectrometry
3 Circulating RNAs
miRNAs lncRNAs mRNAs
4 Circulating Tumour Cellsbull Shed from primary or metastatic lesions
bull Often low abundance
bull Very rare in healthy individuals
bull Require immediate processing
5 Exosomesbull Protects RNA (miRNA lncRNA) DNA
Proteins
Chin J Cancer (2016) Apr 735(1)36Translat Cancer Res (2015) 4 280ndash290
Technology breakthrough Next generation sequencing
ddPCR Unprecedented sensitivity
Multiple targets simultaneously
More parameters to assess
Improved collection Streck tubes (1 W room temperature)
Bioinformatics
Cancer Monitor treatmentsurgery success
Early detection of recurrence
Prognosis
Diagnosis
Prenatal screening
Transplantation rejection
Pharmacogenomics
Apoptotic cell
necrotic cell
Cell-free DNA
Can analyze
1 cfDNA levels2 cfDNA integrity 3 CpG island (promoter) methylation 4 Copy number variation5 Mutations
Sequencing
screening for CNA
screening for mutations
Murtaza Nature 2013
Schuumltz Clin Chem 2015
Droplet digital PCR (ddPCR)
targeted SNPs
Oxnard Clin Cancer Res 2014
Loacutepez Int J Mol Sci 2016
Thress Nature Medicine 2015
Gao J Thorac Oncol 2010
Quantitative allele-specific real-
time PCR (Idylla)
Janku Mol Cancer Ther 2016
Competitive allele-specific TaqMan
PCR (cast-PCR)
Ashida Int J Clin Oncol 2016
Co-amplification at lower
denaturation temperature (COLD)-
PCR
Freidin Clin Chem 2015
BEAMing assay Diehl PNAS 2005
cfDNA Technology platforms
McDermott U (2011) N Eng J Med 364(4)340-50
On the basis of a tumor-biopsy sample massively parallel paired-
end sequencing detects chromosomal rearrangements that can be used to monitor relapse or response to treatment from serial blood samples from the patient
Assessment of a limited number of chromosomal structural instabilities by use of massive parallel sequencing of cfDNA was sufficient to distinguish between prostate cancer and controls
Pantel et al (2010) Trends in Molecular Med
Technologies for Isolating CTC
BREAST CANCER (bone marrow and peripheral blood)
bull Reliable prognostic factor bull Presence of CTC after neo-adjuvant chemotherapy indicates a
high risk for relapse and deathbull Included in ASCO staging M0(i+)
COLORECTAL CANCERDetection of CTC in peripheral blood of patients with resectable colorectal liver metastases or widespread mCRC is associated with disease progression and poor survival
Clinical Utility of Circulating Tumor Cells
Predictive of progression-free survival and overall survival in patients with
biochemical failure
The change in the number of CTC correlates with disease progression
Yu et al (2011) J Cell Biol
bull HER-2 and ERPR status in CTC
bull EMT and stem cell markers
The US-Canada border
What are miRNAs
bull Single-stranded 20-23 nucleotide RNA fragments
bull Do not code for proteins
bull Post-transcriptional regulators
mRNA degradation Translational inhibition
ldquosmall RNAs with a big role in gene regulationrdquoHe L and Hannon GJ Nature reviews genetics 5522-531 2004
A signature that can reliably distinguish normal and cancer
New diagnostic markers
miRNA Dysregulation In ccRCC
White et al J Urol 2011
Chen et al Trends in Cell Biology 2012
Circulating miRNAs
Butz et al Eu Urol Focus in press
Non-invasive urine biomarkers
p= 0016
p= 0007
p= 0033
p= 0033
p= 0019p= 012
p= 0020
p= 0146
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Clin Chem (2016) Jun 3Dis Markers (2015)2015251403J Proteomics (2014) Feb 269844-58
1 Cell-free DNAbull DNA fragmentsbull From necrotic or apoptotic cells
lymphocytesbull Found in urine serum plasmabull Multiple applicationsbull Short half life
2 Proteinspeptidesbull Quantitative global assessment
Label-free mass spectrometry
3 Circulating RNAs
miRNAs lncRNAs mRNAs
4 Circulating Tumour Cellsbull Shed from primary or metastatic lesions
bull Often low abundance
bull Very rare in healthy individuals
bull Require immediate processing
5 Exosomesbull Protects RNA (miRNA lncRNA) DNA
Proteins
Chin J Cancer (2016) Apr 735(1)36Translat Cancer Res (2015) 4 280ndash290
Technology breakthrough Next generation sequencing
ddPCR Unprecedented sensitivity
Multiple targets simultaneously
More parameters to assess
Improved collection Streck tubes (1 W room temperature)
Bioinformatics
Cancer Monitor treatmentsurgery success
Early detection of recurrence
Prognosis
Diagnosis
Prenatal screening
Transplantation rejection
Pharmacogenomics
Apoptotic cell
necrotic cell
Cell-free DNA
Can analyze
1 cfDNA levels2 cfDNA integrity 3 CpG island (promoter) methylation 4 Copy number variation5 Mutations
Sequencing
screening for CNA
screening for mutations
Murtaza Nature 2013
Schuumltz Clin Chem 2015
Droplet digital PCR (ddPCR)
targeted SNPs
Oxnard Clin Cancer Res 2014
Loacutepez Int J Mol Sci 2016
Thress Nature Medicine 2015
Gao J Thorac Oncol 2010
Quantitative allele-specific real-
time PCR (Idylla)
Janku Mol Cancer Ther 2016
Competitive allele-specific TaqMan
PCR (cast-PCR)
Ashida Int J Clin Oncol 2016
Co-amplification at lower
denaturation temperature (COLD)-
PCR
Freidin Clin Chem 2015
BEAMing assay Diehl PNAS 2005
cfDNA Technology platforms
McDermott U (2011) N Eng J Med 364(4)340-50
On the basis of a tumor-biopsy sample massively parallel paired-
end sequencing detects chromosomal rearrangements that can be used to monitor relapse or response to treatment from serial blood samples from the patient
Assessment of a limited number of chromosomal structural instabilities by use of massive parallel sequencing of cfDNA was sufficient to distinguish between prostate cancer and controls
Pantel et al (2010) Trends in Molecular Med
Technologies for Isolating CTC
BREAST CANCER (bone marrow and peripheral blood)
bull Reliable prognostic factor bull Presence of CTC after neo-adjuvant chemotherapy indicates a
high risk for relapse and deathbull Included in ASCO staging M0(i+)
COLORECTAL CANCERDetection of CTC in peripheral blood of patients with resectable colorectal liver metastases or widespread mCRC is associated with disease progression and poor survival
Clinical Utility of Circulating Tumor Cells
Predictive of progression-free survival and overall survival in patients with
biochemical failure
The change in the number of CTC correlates with disease progression
Yu et al (2011) J Cell Biol
bull HER-2 and ERPR status in CTC
bull EMT and stem cell markers
The US-Canada border
What are miRNAs
bull Single-stranded 20-23 nucleotide RNA fragments
bull Do not code for proteins
bull Post-transcriptional regulators
mRNA degradation Translational inhibition
ldquosmall RNAs with a big role in gene regulationrdquoHe L and Hannon GJ Nature reviews genetics 5522-531 2004
A signature that can reliably distinguish normal and cancer
New diagnostic markers
miRNA Dysregulation In ccRCC
White et al J Urol 2011
Chen et al Trends in Cell Biology 2012
Circulating miRNAs
Butz et al Eu Urol Focus in press
Non-invasive urine biomarkers
p= 0016
p= 0007
p= 0033
p= 0033
p= 0019p= 012
p= 0020
p= 0146
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
4 Circulating Tumour Cellsbull Shed from primary or metastatic lesions
bull Often low abundance
bull Very rare in healthy individuals
bull Require immediate processing
5 Exosomesbull Protects RNA (miRNA lncRNA) DNA
Proteins
Chin J Cancer (2016) Apr 735(1)36Translat Cancer Res (2015) 4 280ndash290
Technology breakthrough Next generation sequencing
ddPCR Unprecedented sensitivity
Multiple targets simultaneously
More parameters to assess
Improved collection Streck tubes (1 W room temperature)
Bioinformatics
Cancer Monitor treatmentsurgery success
Early detection of recurrence
Prognosis
Diagnosis
Prenatal screening
Transplantation rejection
Pharmacogenomics
Apoptotic cell
necrotic cell
Cell-free DNA
Can analyze
1 cfDNA levels2 cfDNA integrity 3 CpG island (promoter) methylation 4 Copy number variation5 Mutations
Sequencing
screening for CNA
screening for mutations
Murtaza Nature 2013
Schuumltz Clin Chem 2015
Droplet digital PCR (ddPCR)
targeted SNPs
Oxnard Clin Cancer Res 2014
Loacutepez Int J Mol Sci 2016
Thress Nature Medicine 2015
Gao J Thorac Oncol 2010
Quantitative allele-specific real-
time PCR (Idylla)
Janku Mol Cancer Ther 2016
Competitive allele-specific TaqMan
PCR (cast-PCR)
Ashida Int J Clin Oncol 2016
Co-amplification at lower
denaturation temperature (COLD)-
PCR
Freidin Clin Chem 2015
BEAMing assay Diehl PNAS 2005
cfDNA Technology platforms
McDermott U (2011) N Eng J Med 364(4)340-50
On the basis of a tumor-biopsy sample massively parallel paired-
end sequencing detects chromosomal rearrangements that can be used to monitor relapse or response to treatment from serial blood samples from the patient
Assessment of a limited number of chromosomal structural instabilities by use of massive parallel sequencing of cfDNA was sufficient to distinguish between prostate cancer and controls
Pantel et al (2010) Trends in Molecular Med
Technologies for Isolating CTC
BREAST CANCER (bone marrow and peripheral blood)
bull Reliable prognostic factor bull Presence of CTC after neo-adjuvant chemotherapy indicates a
high risk for relapse and deathbull Included in ASCO staging M0(i+)
COLORECTAL CANCERDetection of CTC in peripheral blood of patients with resectable colorectal liver metastases or widespread mCRC is associated with disease progression and poor survival
Clinical Utility of Circulating Tumor Cells
Predictive of progression-free survival and overall survival in patients with
biochemical failure
The change in the number of CTC correlates with disease progression
Yu et al (2011) J Cell Biol
bull HER-2 and ERPR status in CTC
bull EMT and stem cell markers
The US-Canada border
What are miRNAs
bull Single-stranded 20-23 nucleotide RNA fragments
bull Do not code for proteins
bull Post-transcriptional regulators
mRNA degradation Translational inhibition
ldquosmall RNAs with a big role in gene regulationrdquoHe L and Hannon GJ Nature reviews genetics 5522-531 2004
A signature that can reliably distinguish normal and cancer
New diagnostic markers
miRNA Dysregulation In ccRCC
White et al J Urol 2011
Chen et al Trends in Cell Biology 2012
Circulating miRNAs
Butz et al Eu Urol Focus in press
Non-invasive urine biomarkers
p= 0016
p= 0007
p= 0033
p= 0033
p= 0019p= 012
p= 0020
p= 0146
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Technology breakthrough Next generation sequencing
ddPCR Unprecedented sensitivity
Multiple targets simultaneously
More parameters to assess
Improved collection Streck tubes (1 W room temperature)
Bioinformatics
Cancer Monitor treatmentsurgery success
Early detection of recurrence
Prognosis
Diagnosis
Prenatal screening
Transplantation rejection
Pharmacogenomics
Apoptotic cell
necrotic cell
Cell-free DNA
Can analyze
1 cfDNA levels2 cfDNA integrity 3 CpG island (promoter) methylation 4 Copy number variation5 Mutations
Sequencing
screening for CNA
screening for mutations
Murtaza Nature 2013
Schuumltz Clin Chem 2015
Droplet digital PCR (ddPCR)
targeted SNPs
Oxnard Clin Cancer Res 2014
Loacutepez Int J Mol Sci 2016
Thress Nature Medicine 2015
Gao J Thorac Oncol 2010
Quantitative allele-specific real-
time PCR (Idylla)
Janku Mol Cancer Ther 2016
Competitive allele-specific TaqMan
PCR (cast-PCR)
Ashida Int J Clin Oncol 2016
Co-amplification at lower
denaturation temperature (COLD)-
PCR
Freidin Clin Chem 2015
BEAMing assay Diehl PNAS 2005
cfDNA Technology platforms
McDermott U (2011) N Eng J Med 364(4)340-50
On the basis of a tumor-biopsy sample massively parallel paired-
end sequencing detects chromosomal rearrangements that can be used to monitor relapse or response to treatment from serial blood samples from the patient
Assessment of a limited number of chromosomal structural instabilities by use of massive parallel sequencing of cfDNA was sufficient to distinguish between prostate cancer and controls
Pantel et al (2010) Trends in Molecular Med
Technologies for Isolating CTC
BREAST CANCER (bone marrow and peripheral blood)
bull Reliable prognostic factor bull Presence of CTC after neo-adjuvant chemotherapy indicates a
high risk for relapse and deathbull Included in ASCO staging M0(i+)
COLORECTAL CANCERDetection of CTC in peripheral blood of patients with resectable colorectal liver metastases or widespread mCRC is associated with disease progression and poor survival
Clinical Utility of Circulating Tumor Cells
Predictive of progression-free survival and overall survival in patients with
biochemical failure
The change in the number of CTC correlates with disease progression
Yu et al (2011) J Cell Biol
bull HER-2 and ERPR status in CTC
bull EMT and stem cell markers
The US-Canada border
What are miRNAs
bull Single-stranded 20-23 nucleotide RNA fragments
bull Do not code for proteins
bull Post-transcriptional regulators
mRNA degradation Translational inhibition
ldquosmall RNAs with a big role in gene regulationrdquoHe L and Hannon GJ Nature reviews genetics 5522-531 2004
A signature that can reliably distinguish normal and cancer
New diagnostic markers
miRNA Dysregulation In ccRCC
White et al J Urol 2011
Chen et al Trends in Cell Biology 2012
Circulating miRNAs
Butz et al Eu Urol Focus in press
Non-invasive urine biomarkers
p= 0016
p= 0007
p= 0033
p= 0033
p= 0019p= 012
p= 0020
p= 0146
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Cancer Monitor treatmentsurgery success
Early detection of recurrence
Prognosis
Diagnosis
Prenatal screening
Transplantation rejection
Pharmacogenomics
Apoptotic cell
necrotic cell
Cell-free DNA
Can analyze
1 cfDNA levels2 cfDNA integrity 3 CpG island (promoter) methylation 4 Copy number variation5 Mutations
Sequencing
screening for CNA
screening for mutations
Murtaza Nature 2013
Schuumltz Clin Chem 2015
Droplet digital PCR (ddPCR)
targeted SNPs
Oxnard Clin Cancer Res 2014
Loacutepez Int J Mol Sci 2016
Thress Nature Medicine 2015
Gao J Thorac Oncol 2010
Quantitative allele-specific real-
time PCR (Idylla)
Janku Mol Cancer Ther 2016
Competitive allele-specific TaqMan
PCR (cast-PCR)
Ashida Int J Clin Oncol 2016
Co-amplification at lower
denaturation temperature (COLD)-
PCR
Freidin Clin Chem 2015
BEAMing assay Diehl PNAS 2005
cfDNA Technology platforms
McDermott U (2011) N Eng J Med 364(4)340-50
On the basis of a tumor-biopsy sample massively parallel paired-
end sequencing detects chromosomal rearrangements that can be used to monitor relapse or response to treatment from serial blood samples from the patient
Assessment of a limited number of chromosomal structural instabilities by use of massive parallel sequencing of cfDNA was sufficient to distinguish between prostate cancer and controls
Pantel et al (2010) Trends in Molecular Med
Technologies for Isolating CTC
BREAST CANCER (bone marrow and peripheral blood)
bull Reliable prognostic factor bull Presence of CTC after neo-adjuvant chemotherapy indicates a
high risk for relapse and deathbull Included in ASCO staging M0(i+)
COLORECTAL CANCERDetection of CTC in peripheral blood of patients with resectable colorectal liver metastases or widespread mCRC is associated with disease progression and poor survival
Clinical Utility of Circulating Tumor Cells
Predictive of progression-free survival and overall survival in patients with
biochemical failure
The change in the number of CTC correlates with disease progression
Yu et al (2011) J Cell Biol
bull HER-2 and ERPR status in CTC
bull EMT and stem cell markers
The US-Canada border
What are miRNAs
bull Single-stranded 20-23 nucleotide RNA fragments
bull Do not code for proteins
bull Post-transcriptional regulators
mRNA degradation Translational inhibition
ldquosmall RNAs with a big role in gene regulationrdquoHe L and Hannon GJ Nature reviews genetics 5522-531 2004
A signature that can reliably distinguish normal and cancer
New diagnostic markers
miRNA Dysregulation In ccRCC
White et al J Urol 2011
Chen et al Trends in Cell Biology 2012
Circulating miRNAs
Butz et al Eu Urol Focus in press
Non-invasive urine biomarkers
p= 0016
p= 0007
p= 0033
p= 0033
p= 0019p= 012
p= 0020
p= 0146
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Apoptotic cell
necrotic cell
Cell-free DNA
Can analyze
1 cfDNA levels2 cfDNA integrity 3 CpG island (promoter) methylation 4 Copy number variation5 Mutations
Sequencing
screening for CNA
screening for mutations
Murtaza Nature 2013
Schuumltz Clin Chem 2015
Droplet digital PCR (ddPCR)
targeted SNPs
Oxnard Clin Cancer Res 2014
Loacutepez Int J Mol Sci 2016
Thress Nature Medicine 2015
Gao J Thorac Oncol 2010
Quantitative allele-specific real-
time PCR (Idylla)
Janku Mol Cancer Ther 2016
Competitive allele-specific TaqMan
PCR (cast-PCR)
Ashida Int J Clin Oncol 2016
Co-amplification at lower
denaturation temperature (COLD)-
PCR
Freidin Clin Chem 2015
BEAMing assay Diehl PNAS 2005
cfDNA Technology platforms
McDermott U (2011) N Eng J Med 364(4)340-50
On the basis of a tumor-biopsy sample massively parallel paired-
end sequencing detects chromosomal rearrangements that can be used to monitor relapse or response to treatment from serial blood samples from the patient
Assessment of a limited number of chromosomal structural instabilities by use of massive parallel sequencing of cfDNA was sufficient to distinguish between prostate cancer and controls
Pantel et al (2010) Trends in Molecular Med
Technologies for Isolating CTC
BREAST CANCER (bone marrow and peripheral blood)
bull Reliable prognostic factor bull Presence of CTC after neo-adjuvant chemotherapy indicates a
high risk for relapse and deathbull Included in ASCO staging M0(i+)
COLORECTAL CANCERDetection of CTC in peripheral blood of patients with resectable colorectal liver metastases or widespread mCRC is associated with disease progression and poor survival
Clinical Utility of Circulating Tumor Cells
Predictive of progression-free survival and overall survival in patients with
biochemical failure
The change in the number of CTC correlates with disease progression
Yu et al (2011) J Cell Biol
bull HER-2 and ERPR status in CTC
bull EMT and stem cell markers
The US-Canada border
What are miRNAs
bull Single-stranded 20-23 nucleotide RNA fragments
bull Do not code for proteins
bull Post-transcriptional regulators
mRNA degradation Translational inhibition
ldquosmall RNAs with a big role in gene regulationrdquoHe L and Hannon GJ Nature reviews genetics 5522-531 2004
A signature that can reliably distinguish normal and cancer
New diagnostic markers
miRNA Dysregulation In ccRCC
White et al J Urol 2011
Chen et al Trends in Cell Biology 2012
Circulating miRNAs
Butz et al Eu Urol Focus in press
Non-invasive urine biomarkers
p= 0016
p= 0007
p= 0033
p= 0033
p= 0019p= 012
p= 0020
p= 0146
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Sequencing
screening for CNA
screening for mutations
Murtaza Nature 2013
Schuumltz Clin Chem 2015
Droplet digital PCR (ddPCR)
targeted SNPs
Oxnard Clin Cancer Res 2014
Loacutepez Int J Mol Sci 2016
Thress Nature Medicine 2015
Gao J Thorac Oncol 2010
Quantitative allele-specific real-
time PCR (Idylla)
Janku Mol Cancer Ther 2016
Competitive allele-specific TaqMan
PCR (cast-PCR)
Ashida Int J Clin Oncol 2016
Co-amplification at lower
denaturation temperature (COLD)-
PCR
Freidin Clin Chem 2015
BEAMing assay Diehl PNAS 2005
cfDNA Technology platforms
McDermott U (2011) N Eng J Med 364(4)340-50
On the basis of a tumor-biopsy sample massively parallel paired-
end sequencing detects chromosomal rearrangements that can be used to monitor relapse or response to treatment from serial blood samples from the patient
Assessment of a limited number of chromosomal structural instabilities by use of massive parallel sequencing of cfDNA was sufficient to distinguish between prostate cancer and controls
Pantel et al (2010) Trends in Molecular Med
Technologies for Isolating CTC
BREAST CANCER (bone marrow and peripheral blood)
bull Reliable prognostic factor bull Presence of CTC after neo-adjuvant chemotherapy indicates a
high risk for relapse and deathbull Included in ASCO staging M0(i+)
COLORECTAL CANCERDetection of CTC in peripheral blood of patients with resectable colorectal liver metastases or widespread mCRC is associated with disease progression and poor survival
Clinical Utility of Circulating Tumor Cells
Predictive of progression-free survival and overall survival in patients with
biochemical failure
The change in the number of CTC correlates with disease progression
Yu et al (2011) J Cell Biol
bull HER-2 and ERPR status in CTC
bull EMT and stem cell markers
The US-Canada border
What are miRNAs
bull Single-stranded 20-23 nucleotide RNA fragments
bull Do not code for proteins
bull Post-transcriptional regulators
mRNA degradation Translational inhibition
ldquosmall RNAs with a big role in gene regulationrdquoHe L and Hannon GJ Nature reviews genetics 5522-531 2004
A signature that can reliably distinguish normal and cancer
New diagnostic markers
miRNA Dysregulation In ccRCC
White et al J Urol 2011
Chen et al Trends in Cell Biology 2012
Circulating miRNAs
Butz et al Eu Urol Focus in press
Non-invasive urine biomarkers
p= 0016
p= 0007
p= 0033
p= 0033
p= 0019p= 012
p= 0020
p= 0146
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
McDermott U (2011) N Eng J Med 364(4)340-50
On the basis of a tumor-biopsy sample massively parallel paired-
end sequencing detects chromosomal rearrangements that can be used to monitor relapse or response to treatment from serial blood samples from the patient
Assessment of a limited number of chromosomal structural instabilities by use of massive parallel sequencing of cfDNA was sufficient to distinguish between prostate cancer and controls
Pantel et al (2010) Trends in Molecular Med
Technologies for Isolating CTC
BREAST CANCER (bone marrow and peripheral blood)
bull Reliable prognostic factor bull Presence of CTC after neo-adjuvant chemotherapy indicates a
high risk for relapse and deathbull Included in ASCO staging M0(i+)
COLORECTAL CANCERDetection of CTC in peripheral blood of patients with resectable colorectal liver metastases or widespread mCRC is associated with disease progression and poor survival
Clinical Utility of Circulating Tumor Cells
Predictive of progression-free survival and overall survival in patients with
biochemical failure
The change in the number of CTC correlates with disease progression
Yu et al (2011) J Cell Biol
bull HER-2 and ERPR status in CTC
bull EMT and stem cell markers
The US-Canada border
What are miRNAs
bull Single-stranded 20-23 nucleotide RNA fragments
bull Do not code for proteins
bull Post-transcriptional regulators
mRNA degradation Translational inhibition
ldquosmall RNAs with a big role in gene regulationrdquoHe L and Hannon GJ Nature reviews genetics 5522-531 2004
A signature that can reliably distinguish normal and cancer
New diagnostic markers
miRNA Dysregulation In ccRCC
White et al J Urol 2011
Chen et al Trends in Cell Biology 2012
Circulating miRNAs
Butz et al Eu Urol Focus in press
Non-invasive urine biomarkers
p= 0016
p= 0007
p= 0033
p= 0033
p= 0019p= 012
p= 0020
p= 0146
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Assessment of a limited number of chromosomal structural instabilities by use of massive parallel sequencing of cfDNA was sufficient to distinguish between prostate cancer and controls
Pantel et al (2010) Trends in Molecular Med
Technologies for Isolating CTC
BREAST CANCER (bone marrow and peripheral blood)
bull Reliable prognostic factor bull Presence of CTC after neo-adjuvant chemotherapy indicates a
high risk for relapse and deathbull Included in ASCO staging M0(i+)
COLORECTAL CANCERDetection of CTC in peripheral blood of patients with resectable colorectal liver metastases or widespread mCRC is associated with disease progression and poor survival
Clinical Utility of Circulating Tumor Cells
Predictive of progression-free survival and overall survival in patients with
biochemical failure
The change in the number of CTC correlates with disease progression
Yu et al (2011) J Cell Biol
bull HER-2 and ERPR status in CTC
bull EMT and stem cell markers
The US-Canada border
What are miRNAs
bull Single-stranded 20-23 nucleotide RNA fragments
bull Do not code for proteins
bull Post-transcriptional regulators
mRNA degradation Translational inhibition
ldquosmall RNAs with a big role in gene regulationrdquoHe L and Hannon GJ Nature reviews genetics 5522-531 2004
A signature that can reliably distinguish normal and cancer
New diagnostic markers
miRNA Dysregulation In ccRCC
White et al J Urol 2011
Chen et al Trends in Cell Biology 2012
Circulating miRNAs
Butz et al Eu Urol Focus in press
Non-invasive urine biomarkers
p= 0016
p= 0007
p= 0033
p= 0033
p= 0019p= 012
p= 0020
p= 0146
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Pantel et al (2010) Trends in Molecular Med
Technologies for Isolating CTC
BREAST CANCER (bone marrow and peripheral blood)
bull Reliable prognostic factor bull Presence of CTC after neo-adjuvant chemotherapy indicates a
high risk for relapse and deathbull Included in ASCO staging M0(i+)
COLORECTAL CANCERDetection of CTC in peripheral blood of patients with resectable colorectal liver metastases or widespread mCRC is associated with disease progression and poor survival
Clinical Utility of Circulating Tumor Cells
Predictive of progression-free survival and overall survival in patients with
biochemical failure
The change in the number of CTC correlates with disease progression
Yu et al (2011) J Cell Biol
bull HER-2 and ERPR status in CTC
bull EMT and stem cell markers
The US-Canada border
What are miRNAs
bull Single-stranded 20-23 nucleotide RNA fragments
bull Do not code for proteins
bull Post-transcriptional regulators
mRNA degradation Translational inhibition
ldquosmall RNAs with a big role in gene regulationrdquoHe L and Hannon GJ Nature reviews genetics 5522-531 2004
A signature that can reliably distinguish normal and cancer
New diagnostic markers
miRNA Dysregulation In ccRCC
White et al J Urol 2011
Chen et al Trends in Cell Biology 2012
Circulating miRNAs
Butz et al Eu Urol Focus in press
Non-invasive urine biomarkers
p= 0016
p= 0007
p= 0033
p= 0033
p= 0019p= 012
p= 0020
p= 0146
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
BREAST CANCER (bone marrow and peripheral blood)
bull Reliable prognostic factor bull Presence of CTC after neo-adjuvant chemotherapy indicates a
high risk for relapse and deathbull Included in ASCO staging M0(i+)
COLORECTAL CANCERDetection of CTC in peripheral blood of patients with resectable colorectal liver metastases or widespread mCRC is associated with disease progression and poor survival
Clinical Utility of Circulating Tumor Cells
Predictive of progression-free survival and overall survival in patients with
biochemical failure
The change in the number of CTC correlates with disease progression
Yu et al (2011) J Cell Biol
bull HER-2 and ERPR status in CTC
bull EMT and stem cell markers
The US-Canada border
What are miRNAs
bull Single-stranded 20-23 nucleotide RNA fragments
bull Do not code for proteins
bull Post-transcriptional regulators
mRNA degradation Translational inhibition
ldquosmall RNAs with a big role in gene regulationrdquoHe L and Hannon GJ Nature reviews genetics 5522-531 2004
A signature that can reliably distinguish normal and cancer
New diagnostic markers
miRNA Dysregulation In ccRCC
White et al J Urol 2011
Chen et al Trends in Cell Biology 2012
Circulating miRNAs
Butz et al Eu Urol Focus in press
Non-invasive urine biomarkers
p= 0016
p= 0007
p= 0033
p= 0033
p= 0019p= 012
p= 0020
p= 0146
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Predictive of progression-free survival and overall survival in patients with
biochemical failure
The change in the number of CTC correlates with disease progression
Yu et al (2011) J Cell Biol
bull HER-2 and ERPR status in CTC
bull EMT and stem cell markers
The US-Canada border
What are miRNAs
bull Single-stranded 20-23 nucleotide RNA fragments
bull Do not code for proteins
bull Post-transcriptional regulators
mRNA degradation Translational inhibition
ldquosmall RNAs with a big role in gene regulationrdquoHe L and Hannon GJ Nature reviews genetics 5522-531 2004
A signature that can reliably distinguish normal and cancer
New diagnostic markers
miRNA Dysregulation In ccRCC
White et al J Urol 2011
Chen et al Trends in Cell Biology 2012
Circulating miRNAs
Butz et al Eu Urol Focus in press
Non-invasive urine biomarkers
p= 0016
p= 0007
p= 0033
p= 0033
p= 0019p= 012
p= 0020
p= 0146
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Yu et al (2011) J Cell Biol
bull HER-2 and ERPR status in CTC
bull EMT and stem cell markers
The US-Canada border
What are miRNAs
bull Single-stranded 20-23 nucleotide RNA fragments
bull Do not code for proteins
bull Post-transcriptional regulators
mRNA degradation Translational inhibition
ldquosmall RNAs with a big role in gene regulationrdquoHe L and Hannon GJ Nature reviews genetics 5522-531 2004
A signature that can reliably distinguish normal and cancer
New diagnostic markers
miRNA Dysregulation In ccRCC
White et al J Urol 2011
Chen et al Trends in Cell Biology 2012
Circulating miRNAs
Butz et al Eu Urol Focus in press
Non-invasive urine biomarkers
p= 0016
p= 0007
p= 0033
p= 0033
p= 0019p= 012
p= 0020
p= 0146
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
The US-Canada border
What are miRNAs
bull Single-stranded 20-23 nucleotide RNA fragments
bull Do not code for proteins
bull Post-transcriptional regulators
mRNA degradation Translational inhibition
ldquosmall RNAs with a big role in gene regulationrdquoHe L and Hannon GJ Nature reviews genetics 5522-531 2004
A signature that can reliably distinguish normal and cancer
New diagnostic markers
miRNA Dysregulation In ccRCC
White et al J Urol 2011
Chen et al Trends in Cell Biology 2012
Circulating miRNAs
Butz et al Eu Urol Focus in press
Non-invasive urine biomarkers
p= 0016
p= 0007
p= 0033
p= 0033
p= 0019p= 012
p= 0020
p= 0146
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
What are miRNAs
bull Single-stranded 20-23 nucleotide RNA fragments
bull Do not code for proteins
bull Post-transcriptional regulators
mRNA degradation Translational inhibition
ldquosmall RNAs with a big role in gene regulationrdquoHe L and Hannon GJ Nature reviews genetics 5522-531 2004
A signature that can reliably distinguish normal and cancer
New diagnostic markers
miRNA Dysregulation In ccRCC
White et al J Urol 2011
Chen et al Trends in Cell Biology 2012
Circulating miRNAs
Butz et al Eu Urol Focus in press
Non-invasive urine biomarkers
p= 0016
p= 0007
p= 0033
p= 0033
p= 0019p= 012
p= 0020
p= 0146
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
A signature that can reliably distinguish normal and cancer
New diagnostic markers
miRNA Dysregulation In ccRCC
White et al J Urol 2011
Chen et al Trends in Cell Biology 2012
Circulating miRNAs
Butz et al Eu Urol Focus in press
Non-invasive urine biomarkers
p= 0016
p= 0007
p= 0033
p= 0033
p= 0019p= 012
p= 0020
p= 0146
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Chen et al Trends in Cell Biology 2012
Circulating miRNAs
Butz et al Eu Urol Focus in press
Non-invasive urine biomarkers
p= 0016
p= 0007
p= 0033
p= 0033
p= 0019p= 012
p= 0020
p= 0146
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Butz et al Eu Urol Focus in press
Non-invasive urine biomarkers
p= 0016
p= 0007
p= 0033
p= 0033
p= 0019p= 012
p= 0020
p= 0146
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
p= 0016
p= 0007
p= 0033
p= 0033
p= 0019p= 012
p= 0020
p= 0146
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
p= 0039 p= 0030
p= 0034
p= 0032p= 0041
p= 0036 p= 0029 p= 0060
hsa-miR-10a (one-way ANOVA)
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
0
02
04
06
08
1
12
RQ
Val
ue
s
miRNA
Dysregulation of miRNAs by Gleason Grade
GleasonGrade 3
GleasonGrade 4
GleasonGrade 5
Lichner et al J Pathol 2015 Oct237(2)226-37
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
3+3 = Grade group 1
3+4 = Grade group 2
4+3 = Grade group 3
ge 4+4 = grade group 4
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
hsa-miR-30c-000419
Area under ROC curve = 0912
Of the 27 subjects with Ct values of 35 or greater in urine samples all 27 had modified Gleason scores of 2 3 or 4 (100 PPV)
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
hsa-miR-30c-000419
Area under ROC curve = 0910
Of the 32 subjects with Ct values under 292 in serum 31 had modified Gleason scores of 1 or 2 (97 NPV)
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
PCa prostate cancerASC asymptomatic control
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Non-coding RNA
Overexpressed in PCa (sensitivity 66 specificity 76)
The PROGENSA PCA3 Assay
FDA-approved
Measures PCA3 and PSA RNA and calculates a PCA3 Score in post-DRE first catch urine
To aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
FDA approval for first liquid biopsy test for NSCLC in May 2016
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Fully represents tumor Solves heterogeneity
cfDNA vs ctDNA what are we capturing
Where is it coming from primary vs metastasis
Is the primary different from metastasis
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
1 Discovery cohorts typically insufficiently powered
1 Standard specimen collection and handling
2 Standard approach to normalization
3 Lead-time bias
4 Platform reproducibility
Rapisuwon S (2016) Comput Struct Biotechnol J 114211-22
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Gene Candidate
Test grade reagents
Initial clinical validation
Secondary clinical validation
High grade reagents developed
Regulatory approval
Cost effective clinical decision research
Guidelinesimplementation
Outcomes research amp new indications
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Tissue-based more specific
But might not be validate
Does it need to be specific
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Integrative personal omics profiling
Individual disease risk predicted from integrated omics data
Follow the genome of one individual over a period of time in health and disease
Molecular changes revealed during different health states
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Analysis of 406 published severe disease mutations 122 (27) of these were either common polymorphisms or lacked direct evidence for pathogenicity
Numerous alleged severe-disease-causing variants were found in the genomes of population controls
Well-powered follow-up validation studies have cast serious doubts on initial reports
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Disease prevalence
1 100000
A test with
999 sensitivity
999 specificity
If you screen 10000000
100 will have the disease
10000 will be false positives
100 patients will be missed
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Genomic measurements is likely to yield unexpected incidental findings for nearly everyone
Patients will be subjected to unnecessary follow-up tests causing additional morbidity
The cost of genomic medicine will increase substantially with little benefit to patients
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Incidental finding unexpected positive findings
Constitutional mutations found in the genes on the minimum list should be reported by the laboratory to the ordering clinician regardless of the indication for sequencing
It is the responsibility of the ordering clinician to provide comprehensive pre- and posttest counseling to the patient
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Free and open access to genome data has had a profoundly positive effect on progress
Technology development must continue to be a major focus of investment
Achieving the promise of new drug targets requires new paradigms of publicndashprivate partnership
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Do not chat until IP or CA in place
Is the invention unique amp novel
What is the value proposition
What is the competition
Pathway to commercialization must be clear
Regulatory and reimburse hurdles
Chungh S (2013) Proteomics 13(15)2324-34
Chungh S (2013) Proteomics 13(15)2324-34
