Bio Marker i

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A biased look at Biomarkers

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Transcript of Bio Marker i

  • A biased look at Biomarkers

  • BioMarkerDefinition:Biomarker is a substance used as an indicator of a biologic state

    Existence of living organisms or biological process. A particular disease state ProteinsNucleic acidsMetabolites: CarbohydratesLipidsSmall molecules

  • BiomarkerDetection of biomarkerDetection of biomarkerQuantitative a link between quantity of the marker and disease Qualitative a link between exist of a marker and diseaseDetection of biomarker diagnosisSelf properties, e.g enzymatic activitiesAntibodies, IHC, ELISA

  • Biomarker & DiagnosisIdeal Marker for diagnosisShould have great sensitivity, specificity, and accuracy in reflecting total disease burden. A tumor marker should also be prognostic of outcome and treatmentBiomarker for ScreeningThe marker must be highly specific, minimize false positive and negativeThe marker must be easily detected without complicated medical procedures. The disease markers released to serum and urine are good targets for application of early screening.The method for screening should be cost effective. The marker must be able to clearly reflect the different stages of the disease (early) Samples for biomarker detectionBlood, urine, or other body fluids samplesTissue samples

  • Prostate Cancer marker PSAPSA is a protein normally made in the prostate gland in ductal cells that make some of the semen. PSA helps to keep the semen liquid. PSA, also known as kallikrein III, seminin, semenogelase, -seminoprotein and P-30 antigen, is a glycoprotein, a serine protease

  • Prostate Cancer Diagnosis with PSACancer of the prostate does not cause any symptoms until it is locally advanced or metastatic. There is a correlation between elevated PSA and prostate cancer. Detection of PSA is a surrogate for early detection of prostate cancer. Large screening trials have shown that PSA nearly doubles the rate of detection when combined with other methods. Based on these data, PSA testing was approved by the US FDA for the screening and early detection of prostate cancer. PSA is also found in the cytoplasm of benign prostate cells. I never dreamed that my discovery four decades ago would lead to such a profit-driven public health disaster." -Richard Ablin (inventor of the PSA test)PSA screening generates ~$1.7 billion annually in the U.S. alone.

  • Sensitivity = the ability of the test to detect the disease (True positive rate)Specificity = the likelihood that your test will be normal if you are disease free (True Negative)

  • A brief aside about Statistics and Probability-Statistics are the formalization of common sense-because they have to handle many different situations, they can be really complicated-they should make you feel really good or really bad about your data

    -People are inherently bad at statisitics and probability Case Study:rate for being HIV positive: 1:10000 false positive rate of HIV test: 1:1000

    If I test positive, what is the chance that I am really HIV negative?

  • -Statistics are the formalization of common sense-because they have to handle many different situations, they can be really complicated-they should make you feel really good or really bad about your data

    -People are inherently bad at statisitics and probability Case Study:rate for being HIV positive: 1:10000 false positive rate of HIV test: 1:1000

    What is the chance that I am HIV negative?

    0.0001 0.001 0.01 0.1 0.9 0.99 0.9999 A brief aside about Statistics and Probability

  • -Statistics are the formalization of common sense-because they have to handle many different situations, they can be really complicated-they should make you feel really good or really bad about your data

    -People are inherently bad at statisitics and probability Case Study:rate for being HIV positive: 1:10000 false positive rate of HIV test: 1:1000

    What is the chance that I am HIV negative?

    0.0001 0.001 0.01 0.1 0.9 0.99 0.9999

    For every 1 True Positive there will be 10 false positives, so my chanceof being Negative is 10/11. A brief aside about Statistics and Probability

  • Rate is 15:10000False Positive Rate is 60:1000

    For every 15 True Positives, there will be 600 False Positives!Chance of being Negative 600/615 = .97Chance of being Positive = .03 (before test chance was 0.015)-Is this true?How about the PSA test?

  • Rate is 15:10000False Positive Rate is 60:1000

    For every 15 True Positives, there will be 610 False Positives!Chance of being Negative 600/615 = .97Chance of being Positive = .03 (before test chance was 0.015)-Is this true?The test will miss 80% of the true positives (sensitivity = 20%) so there will only be 3 True Positives Detected so: Chance of being Negative 600/603 = 0.995 Chance of being True Positive = 0.005

    Follow up for a +HIV test is another blood test.Follow up for +PSA test is tissue biopsy.

    How about the PSA test?

  • By Age 65 the rate of Prostate Cancer climbs to 8:1000 and the test performsmuch better.For every 8 True Positives, there will be 60 False Positives!Chance of being Negative 60/68 = .88Chance of being Positive = .12 (before test chance was 0.015)

    How good does a Biomarker have to be?

  • Prostate Cancer is one of the most frequent cancers (15:10000), mostcancers are much less frequent (1:10000: 1:50000) so a biomarker wouldhave to be much better than the PSA test. It is currently believed that a newbiomarker would need sensitivity and specificity better than 95%.

    How good does a Biomarker have to be?

  • Early Proteomics Base Biomarker workwas based on SELDISELDI can detect 200-300 features in a sample. It has been used to findbiomarkers from everything from blood to tears.

  • Early Biomarker work has largely been discredited-Biomarkers with similar masses kept being rediscovered-When the proteins were identified, they were abundant serum proteins and were from the same proteins-Multi-center studies failed to validate the biomarkers in clinicalsetting

    -Realization that serum and other biofluids are incredibly complex.

    -Realization that serum and other biofluids are incredibly variable and fragile-some strong biomarkers-blood collection tube-# of freeze-thaw cycles-diet

  • Key Concept: Proteins vary widely in concentration

  • Typical Biomarker Discovery studywill take 50 samples per condition.Typically takes 10 samples per conditionto have a 90% chance of finding differencesof 2 times.Validation will take 1000s of samples. Finally the assay will have to be converted to something that can be done ina clinical lab.

  • 2007PCA or other Clustering is used for Biomarker discovery

  • Common Serum Markers for Cancer Diagnosis/prognosis

    AFPCEACA15-3CA19-9CA125PSAPSAfPAPhTGHCGbFerrNSEB2MA2MLungxxxxxxxPancreasxxxxxKidneyxxxxBreastxxxOvarianxxxxxxCervicalxxUterinexxxxProstatexxxxxLiverxxxxxGastroxxxColonxxxxxBladderxBrainxLeukemiaxxxMyelomaxThyroidxxTesticularxxxx

  • Conclusions-Biomarker Discovery is difficult-biofluids are complex-biofluids have a high dynamic range-biomarkers are usually low abundance-even taking proximal fluids typically does not help-the is a lot of person to person variability

    -Most Biomarkers will never become clinically relevant-statistical standards for diagnostic tools is very high-the more prevalent the disease the better the biomarker will perform

    -An MS based biomarker assay is unlikely due to the greater analytical performance of antibody based methods.

    -For a biomarker workflow to be meaningful it must be quantitative!

  • Quantitative ApproachesStable Isotope Labeling methods-adds heavy isotopes to one sample so chemically identical compounds are mass shifted-added to the peptides/proteins using reactive groups-added to the proteins in vivo using heavy amino acids-can be multiplexed

    Label free methods-extracted ion chromatograms-spectral counting

  • ISOTOPE-CODED AFFINITY TAG (ICAT):Label protein samples with heavy and light reagentReagent contains affinity tag and heavy or light isotopesChemically reactive group: forms a covalent bond to the protein or peptideIsotope-labeled linker: heavy or light, depending on which isotope is usedAffinity tag: enables the protein or peptide bearing an ICAT to be isolated by affinity chromatography in a single step

  • Example of an ICAT ReagentBiotin Affinity tag: Binds tightly to streptavidin-agarose resinLinker: Heavy version will have deuteriums at *Light version will have hydrogens at *Reactive group: Thiol-reactive group will bind to Cys

  • The ICAT Reagent

  • How ICAT works?Proteolysis (ie trypsin)Lyse & LabelMIXAffinity isolation on streptavidin beadsQuantificationMSIdentificationMS/MS100m/zm/zLightHeavyNH2-EACDPLR-COOH

  • ICAT Quantitation

  • ICATAdvantages vs. DisadvantagesEstimates relative protein levels between samples with a reasonable level of accuracy (within 10%)

    Can be used on complex mixtures of proteins

    Cys-specific label reduces sample complexity

    Can set up the mass spectrometer to fragment only those peaks with a certain ratioYield and non specificity

    Slight chromatography differences

    Expensive

    Tag fragmentation

    Meaning of relative quantification information

    No presence of cysteine residues or not accessible by ICAT reagent

  • ChargedNeutral lossIsobaric Tag(Total mass = 145)iTRAQ Reagent Design

  • Isobaric Tagging - General Method (4-Plex)

  • Spotfire K-means Clustering of Protein-level Ratios

  • *-TPHPALTEAK-*MS/MS Spectra of a Singly-charged Peptide

  • Summed Ion Intensity (~75,000 Spectra)Reporter Group Placement: Selection of Quiet Region

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Neurobiology I – Bio 334

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