Introduction to Research: The Physician-Scientist Perspective Ross Summer MD.
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Transcript of Introduction to Research: The Physician-Scientist Perspective Ross Summer MD.
Introduction to Research: The Physician-Scientist Perspective
Ross Summer MD
Objectives• Define Biomedical Research• Review the Scientific Method and discuss its
importance to research• Discuss types of biomedical research• Is a career in research right for me? *****• How do I become funded to perform biomedical
research? • Where does the money come from?• Conclusion
What is Biomedical Research?
• The major goal of biomedical research is to solve medical problems by acquiring new knowledge or correcting and integrating previous knowledge.
• The chief characteristics that distinguish research from other methods of acquiring knowledge is that scientists seek to let reality speak for itself.
The Scientific Method• Make an observation: “Most patients with lung fibrosis have a history of smoking
cigarettes.” • Formulate a question: "Why does pulmonary fibrosis occur more often in
smokers?“ This stage involves extensive research and knowledge of the field. • Generate a hypothesis: The hypothesis is a conjecture based on your extensive
knowledge of the field. The hypothesis is very specific. “Downregulation of X in smokers leads to upregulation of TGFbeta and subsequent development of pulmonary fibrosis.
• Test your hypothesis: This is an investigation of whether the real world behaves as predicted by the hypothesis. Importantly, experiments should be designed to minimize possible errors, and this requires expertise.
• Analysis: This involves determining what the results show and deciding on the next actions to take. Interpretation of data is not straight-forward! Depending on either individual biases or the statistical methods used the same results can be interpreted very differently.
Types of Biomedical Research
1. PRECLINICAL RESEARCH. 2. CLINICAL RESEARCH.3. TRANSLATIONAL RESEARCH.
PRECLINICAL RESEARCH is undertaken to increase knowledge about the basic processes of living organisms. Animal models are often used to observe and evaluate those
processes. This type of research provides the foundation upon which other types of research are built.
Pre-clinical Research
Advantage• Can lead to novel
discoveries. • Often cheaper.• Allows for answering
questions faster• Easier to control
environment and confounding variables
• Safer (from human perspective)
Disadvantage• Findings may not be
applicable to humans.• Animal models may not
mimic human disease.• Long-term costs may be
higher.• False discovery rate is high• Morally unacceptable
CLINICAL RESEARCH is patient oriented.
Studies of mechanisms of human disease Studies of therapies or interventions for
disease Studies to develop new technology related to
disease
Clinical research
Advantages• Highly relevant.• Tends to have lower false
discovery rates.
Disadvantages• Costly• Difficult to recruit subjects• Difficult to control variables
(e.g. environmental factors).
• Large genetic diversity among subjects (findings in one population may not be relevant to another).
TRANSLATIONAL goal is to integrate preclinical and clinical research.
Translational Research• This translation may seem like an automatic, but in reality it is a major stumbling
block in science. • T1 research “bench to bedside” – goal is to improve our health through research
and its application.• T2 “beside to the community” - goal is to facilitate the application of research
findings to the community. – Compare efficacy
• Effect of interventions on outcomes in a highly controlled setting– Compare effectiveness
• Effect of interventions on outcomes in an uncontrolled, ‘real world’ setting
– Which drug works on large scale?– Which effective treatment is being used?– How can we get patients/physicians to use a therapy?
How do I determine if a career in research is right for me?
Observation: Remote control car stops working. Question: What is wrong with the remote control car?Hypotheses: (1) The batteries are dead. (2) Maybe I left it out in the rainExperiments: (1) Check the batteries. (2) Check and see if it is wet.Results: New batteries fix the car
Everyone is a born scientist, but …..
……research is not right for everyone
• Before deciding, one must dispel the notion that a career in biomedical research is worthy of special recognition!
You must love it!
Am I willing and able to make additional sacrifices?
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Age
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Figure 1. Average Age of Principal Investigators with MD, MD-PhD, or PhD at the time of First R01 Equivalent Award from NIH, Fiscal Years 1980 to 2011
MD-PhD
MD Only
PhD Only
Courtesy NIH.gov
Do I have the right personality?
Schwartz AJRCCM 2012
Researcher personalities and their impact on research
Research Personalities and their impact on Biomedical Research
False discovery in research
• Amgen found that 47 of 53 “landmark” oncology publications could not be reproduced. Nature 2012
• Bayer found that 43 of 67 oncology and cardiovascular clinical projects were driven by non-reproducible results from academic publications. Nature Reviews Drug Discovery 10, 712 (September 2011)
• Dr. John Ioannidis and his colleagues found that of 432 publications purporting differences in hypertension, multiple sclerosis, or lung cancer, only a small sample were reproducible. Nature Genetics 41, 149 - 155 (2009)
Strategies to reduce false discovery• There must be more opportunities to present negative data. It should be the expectation that negative data will
be presented at conferences and in publications. • Investigators should be required to report all findings, regardless of the outcome. To facilitate this, funding
agencies, reviewers and journal editors must agree that negative data can be just as informative as positive data.• Journal editors must play an active part in initiating a cultural change. There must be mechanisms to report
negative data that are accessible through PubMed or other search engines. There should be links to journal articles in which investigators have reported alternative findings to those in an initial (sometimes considered landmark) publication. One suggestion is to include 'tags' that report whether the key findings of a seminal paper were confirmed.
• There should be transparent opportunities for trainees, technicians and colleagues to discuss and report troubling or unethical behaviors without fearing adverse consequences.
• Greater dialogue should be encouraged between physicians, scientists, patient advocates and patients. Scientists benefit from learning about clinical reality. Physicians need better knowledge of the challenges and limitations of preclinical studies.
• Institutions and committees should give more credit for teaching and mentoring: relying solely on publications in top-tier journals as the benchmark for promotion or grant funding can be misleading, and does not recognize the valuable contributions of great mentors, educators and administrators.
Begley and Ellis et al. Nature Volume: 483, Pages: 531–533 Date published: (29 March 2012
Systems to protect subjects
Pre-clinical• IACUC
Human• IRB
What is the IRB• An Institutional Review Board (IRB) is a review committee established to help protect the rights and welfare of human research subjects.
Regulations require IRB review and approval for research involving human subjects if it is funded or regulated by the federal government. Most research institutions, professional organizations, and scholarly journals apply the same requirements to all human research.
• Federal regulations dictate that the IRB membership will include:• At least five members• Member of both sexes• Members that come from varied professions• At least one member whose primary concerns are in nonscientific areas• At least one member whose primary concerns are in scientific area• At least one member who is not otherwise affiliated with the institution
IACUC• The Institutional Animal Care and Use Committee (IACUC) is a self-
regulating entity that, according to U.S. federal law, must be established by institutions that use laboratory animals for research or instructional purposes to oversee and evaluate all aspects of the institution's animal care and use program.
• Federal regulations dictate that the IRB membership will include:– Doctor of Veterinary Medicine, with training or experience in laboratory
animal sciences and medicine, who has direct or delegated program responsibility for activities involving animals at the institution;
– Practicing scientist experienced in research involving animals;– Member whose primary concerns are in a nonscientific area;– Individual who is not affiliated with the institution in any way other than as a
member of the IACUC, and is not a member of the immediate family of a person who is affiliated with the institution. This individual should represent community interests and concerns.
How does a physician become a funded principal investigator?
It is not easy
What is the typical path to success as a physician scientist?
Where does the money come from?
Conclusion
• The goal of biomedical research is to solve medical problems.
• This is accomplished through pre-clinical, human and translational research.
• The path to becoming a funded physician-scientist is long but very rewarding.
Protecting Research Subjects• Informed consent
• Coercion or undue pressure on volunteers (or on a parent to volunteer his/her child)
• Use of a vulnerable population
• Exploitation of a vulnerable population
• Withholding information
• Withholding available treatment
• Withholding information about risks
• Putting subjects at risk
• Risks to subjects outweigh benefits
• Deception
• Violation of rights
Timeline for becoming a funded principal investigator
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Figure 2. Number of New and Experienced Investigators on R01 Equivalent Grants and New Investigators as a Percentage of All Competing R01 Awardees (FY 1962 - 2011)
Established Investigators
New Investigators
Percent New
Courtesy NIH.gov
DESIGNS/Methodology
• Randomized Interventional Trials– Parallel group – Crossover
• Observational Studies– Prospective– Retrospective– Cohort, case-control, cross-sectional, case-
crossover, nested case-control…
• Meta-analyses– observational analysis of past trials
Non-Interventional Studies
• It’s all about the data
• Match a good question to the right database– Can make the database or acquire one
• Require much more nuanced understanding of statistics and study design than RCTs
• Pro: Perform studies that are not possible/ethical in interventional trials
• Con: Mostly limited to “association” rather than “causation”…
The problem of Confounding• What is confounding?
• The purpose of randomization is eliminate confounding by observed and unobserved variables
• Observational studies cannot eliminate confounding by unrecorded variables
CEO
The Importance of Good Data• A robust database helps mitigate (but not
eliminate) the problem of unobserved confounders
• Robust databases are rare in Critical Illness
Potential Data Sources• Our Clinical Data Warehouse
– Nice robust data is readily available– Always limited generalizability: “single center”
data• Administrative Data
– Medicare, State, National Inpatient data sets– Very generalizable, huge “Ns”– Limited accuracy and ? validity of ICD-9s– Confounding and bias galore
• Hybrid data– Commercial data warehouses, expensive
• Open source clinical trial data– Detailed and accurate, but limited to specific trial
An Approach to ICU Research
• Come up with your question• Do Pilot study using Data Warehouse• Larger confirmatory study w/ Administrative data• If appropriate, Interventional Trial
– Sometimes this is impossible