CONTRIBUTIONS OF DIFFERENT CONTRIBUTIONS OF DIFFERENT TYPES OF EVIDENCE TO THE TYPES OF EVIDENCE TO THE

CONCLUSION OF A VALID CONCLUSION OF A VALID STATISTICAL ASSOCIATION AND STATISTICAL ASSOCIATION AND

JUDGMENT OF CAUSALITYJUDGMENT OF CAUSALITY

Charles H. Hennekens, MD,DrPHSir Richard Doll Research Professor

Charles E. Schmidt College of Biomedical Science &Center of Excellence

Florida Atlantic University (FAU)

• I am funded by the Charles E. Schmidt College of Medicine at Florida Atlantic I am funded by the Charles E. Schmidt College of Medicine at Florida Atlantic University (FAU). I have served as Principal Investigator on two investigator University (FAU). I have served as Principal Investigator on two investigator initiated research grants funded to FAU by Bayer testing the effects of aspirin dose initiated research grants funded to FAU by Bayer testing the effects of aspirin dose on platelet and inflammatory biomarkers as well as nitric oxide formation.on platelet and inflammatory biomarkers as well as nitric oxide formation.

•I serve as an independent scientist in an advisory role to investigators and I serve as an independent scientist in an advisory role to investigators and sponsors as Chair of Data and Safety Monitoring Boards for Actelion, Amgen, sponsors as Chair of Data and Safety Monitoring Boards for Actelion, Amgen, Anthera, Bristol-Myers Squibb, and Sunovion and as a Member of Data and Safety Anthera, Bristol-Myers Squibb, and Sunovion and as a Member of Data and Safety Monitoring Boards for AstraZeneca, Bayer , British Heart Foundation, Canadian Monitoring Boards for AstraZeneca, Bayer , British Heart Foundation, Canadian Institutes of Health Research and Lilly. Institutes of Health Research and Lilly.

•I serve as an independent scientist in an advisory role to the U.S. Food and Drug I serve as an independent scientist in an advisory role to the U.S. Food and Drug Administration, U.S. National Institutes of Health, Children's Services Council of Administration, U.S. National Institutes of Health, Children's Services Council of Palm Beach County and UpToDate.Palm Beach County and UpToDate.

•I serve as an independent scientist in an advisory role to legal counsel for I serve as an independent scientist in an advisory role to legal counsel for GlaxoSmithKline and Stryker. GlaxoSmithKline and Stryker.

•I serve as speaker for the Association for Research in Vision and Ophthalmology, I serve as speaker for the Association for Research in Vision and Ophthalmology, Baptist Health South Florida, National Association for Continuing Education, Baptist Health South Florida, National Association for Continuing Education, PriMed, and the International Atherosclerosis Society.PriMed, and the International Atherosclerosis Society.

•I receive royalties for authorship or editorship of three textbooks.I receive royalties for authorship or editorship of three textbooks.

•I receive royalties as co-inventor on patents concerning inflammatory markers and I receive royalties as co-inventor on patents concerning inflammatory markers and cardiovascular disease which are held by Brigham and Women’s Hospital.cardiovascular disease which are held by Brigham and Women’s Hospital.

•I have an investment management relationship with The West-Bacon Group I have an investment management relationship with The West-Bacon Group within SunTrust Investment Services who has discretionary investment authority.within SunTrust Investment Services who has discretionary investment authority.

•I do not own any common or preferred stock in any pharmaceutical or medical I do not own any common or preferred stock in any pharmaceutical or medical device company. device company.

DisclosureDisclosure

Death is inevitable but premature death is notDeath is inevitable but premature death is not

Sir Richard DollSir Richard Doll

Hennekens CH. Epidemiology in Medicine. Boston, Mass: Little, Brown & Co.;1987.

Totality of EvidenceTotality of Evidence

• Basic research (why)Basic research (why)• Epidemiology (whether)Epidemiology (whether)

– Descriptive studiesDescriptive studies• case reportscase reports• case seriescase series• ecological studiesecological studies

– Analytic studiesAnalytic studies• observationalobservational

– case-controlcase-control– cohortcohort

• randomized trialsrandomized trials

ADVANTAGES AND DISADVANTAGESADVANTAGES AND DISADVANTAGES

Basic ResearchBasic ResearchAdvantage: PrecisionAdvantage: Precision

Disadvantage: Questionable relevance to free living Disadvantage: Questionable relevance to free living humanshumans

EpidemiologyEpidemiologyAdvantage: Relevance to free living humansAdvantage: Relevance to free living humans

Disadvantage: ImprecisionDisadvantage: Imprecision

QUESTIONABLE RELEVANCE OF BASIC QUESTIONABLE RELEVANCE OF BASIC RESEARCH TO FREE LIVING HUMANSRESEARCH TO FREE LIVING HUMANS

Who would have guessed that Homo sapiens Who would have guessed that Homo sapiens would share with the humble guinea pig the would share with the humble guinea pig the unenviable distinction of being unable to unenviable distinction of being unable to synthesize ascorbic acid or with armadillos a synthesize ascorbic acid or with armadillos a susceptibility to the bacterium that causes susceptibility to the bacterium that causes leprosy or that intestinal cancer usually leprosy or that intestinal cancer usually occurs in the large intestine of humans and occurs in the large intestine of humans and the small intestine of sheep?the small intestine of sheep?

Professor John CairnsProfessor John Cairns

QUESTIONABLE RELEVANCE OF BASIC QUESTIONABLE RELEVANCE OF BASIC RESEARCH TO FREE LIVING HUMANSRESEARCH TO FREE LIVING HUMANS

In basic research over 750,000 chemicals have In basic research over 750,000 chemicals have the potential to cause cancer but less than the potential to cause cancer but less than 7500 have any direct relevance to humans7500 have any direct relevance to humans

Professor Sir Richard PetoProfessor Sir Richard Peto

QUESTIONABLE RELEVANCE OF BASIC QUESTIONABLE RELEVANCE OF BASIC RESEARCH TO FREE LIVING HUMANSRESEARCH TO FREE LIVING HUMANS

When the Harvard researcher was asked how to When the Harvard researcher was asked how to explain the discrepancies between the excess explain the discrepancies between the excess bladder cancer among Canadian rats fed 15 gallons bladder cancer among Canadian rats fed 15 gallons of artificial sweeteners daily and no association of artificial sweeteners daily and no association between artificial sweeteners and bladder cancer in between artificial sweeteners and bladder cancer in Massachusetts humans who drank about 1-2 cans of Massachusetts humans who drank about 1-2 cans of soda containing artificial sweeteners daily he replied soda containing artificial sweeteners daily he replied that there must be systematic differences between that there must be systematic differences between the Canadian rats and the Massachusetts humans. the Canadian rats and the Massachusetts humans.

Columbus Georgia LedgerColumbus Georgia Ledger

QUESTIONABLE RELEVANCE OF BASIC QUESTIONABLE RELEVANCE OF BASIC RESEARCH TO FREE LIVING HUMANSRESEARCH TO FREE LIVING HUMANS

I guess it takes a researcher from Harvard to I guess it takes a researcher from Harvard to

put 2 and 2 together.put 2 and 2 together.

The New Yorker MagazineThe New Yorker Magazine

STATISTICAL ASSOCIATION AND CAUSE STATISTICAL ASSOCIATION AND CAUSE AND EFFECT RELATIONSHIPSAND EFFECT RELATIONSHIPS

• Statistical Association: A matter of fact like Statistical Association: A matter of fact like death and taxesdeath and taxes

• Cause and Effect Relationships: A matter of Cause and Effect Relationships: A matter of opinion like truth and beautyopinion like truth and beauty

STATISTICAL ASSOCIATIONSTATISTICAL ASSOCIATION

A valid statistical association can be inferred A valid statistical association can be inferred from an analytic study after exclusion offrom an analytic study after exclusion of

• CHANCE andCHANCE and

• BIAS andBIAS and

• CONFOUNDINGCONFOUNDING

as plausible alternative explanations for the as plausible alternative explanations for the observed findingsobserved findings

CHANCECHANCE

• Chance refers to the probability of findings at Chance refers to the probability of findings at least as extreme as in your data when the least as extreme as in your data when the null hypothesis is truenull hypothesis is true

• Any P value depends on both the magnitude Any P value depends on both the magnitude of association as well as the size of the of association as well as the size of the sample.sample.

• P values and confidence limits evaluate the P values and confidence limits evaluate the role of chance but not bias or confoundingrole of chance but not bias or confounding

Don’t let the glitter of the t-table detract fromDon’t let the glitter of the t-table detract from

the quality of the farethe quality of the fare

Professor Sir Austin Bradford HillProfessor Sir Austin Bradford Hill

BIASBIAS

• Bias may be defined as any systematic error Bias may be defined as any systematic error in an analytic study that results in an incorrect in an analytic study that results in an incorrect estimate of the magnitude of associationestimate of the magnitude of association

• Selection bias refers to any error that arises Selection bias refers to any error that arises in the process of identifying the study in the process of identifying the study populationpopulation

• Observation bias includes any systematic Observation bias includes any systematic error in the measurement of information on error in the measurement of information on exposure or outcome.exposure or outcome.

CONFOUNDINGCONFOUNDING

• Confounding may be viewed as a mixing of Confounding may be viewed as a mixing of the effect of the exposure under study on the the effect of the exposure under study on the disease with that of a third factor.disease with that of a third factor.

• This third factor must be associated with the This third factor must be associated with the exposure and, independent of the exposure, exposure and, independent of the exposure, be a risk factor for the disease. be a risk factor for the disease.

THE NEED FOR LARGE SCALE THE NEED FOR LARGE SCALE RANDOMIZED EVIDENCERANDOMIZED EVIDENCE

•For hypotheses testing of large effects (i.e. smoking and lung cancer For hypotheses testing of large effects (i.e. smoking and lung cancer where RR=20, or even smoking and CHD where RR=2.0) randomized where RR=20, or even smoking and CHD where RR=2.0) randomized

evidence is neither necessary nor desirableevidence is neither necessary nor desirable

•For small to moderate effects (i.e.10-50%) the amount of uncontrolled For small to moderate effects (i.e.10-50%) the amount of uncontrolled and uncontrollable confounding inherent in all case control and cohort and uncontrollable confounding inherent in all case control and cohort studies is as big as the effect size so large scale randomized evidence studies is as big as the effect size so large scale randomized evidence

is crucial. is crucial.

Hennekens CH, DeMets D: The need for large scale randomized Hennekens CH, DeMets D: The need for large scale randomized evidence evidence without undue emphasis on small trials, their meta-analyses or without undue emphasis on small trials, their meta-analyses or subgroup analyses JAMA 2009;302:2361-2362.subgroup analyses JAMA 2009;302:2361-2362.

SUBGROUP ANALYSESSUBGROUP ANALYSES

• Subgroup analyses are no longer randomized and Subgroup analyses are no longer randomized and have lower sample sizes and should be viewed, at have lower sample sizes and should be viewed, at best, as hypothesis formulating and, at worst, as best, as hypothesis formulating and, at worst, as rubbish. The biggest danger in interpretation of rubbish. The biggest danger in interpretation of subgroups is acting as if they provide serious subgroups is acting as if they provide serious evidence. evidence.

• If you torture the data enough they will confess. If you torture the data enough they will confess.

Professor Sir Richard PetoProfessor Sir Richard Peto

Intention to Treat (ITT) Analyses of Intention to Treat (ITT) Analyses of Randomized TrialsRandomized Trials

• A randomized trial tests the offering of the A randomized trial tests the offering of the treatment not the treatmenttreatment not the treatment

• ITT analyses preserve the randomization and ITT analyses preserve the randomization and avoids the introduction of confounders, only avoids the introduction of confounders, only some of which are known and knowablesome of which are known and knowable

Intention to Treat (ITT) and Analyses of Intention to Treat (ITT) and Analyses of Compliers: Coronary Drug Project Trial of Compliers: Coronary Drug Project Trial of

Clofibrate and Mortality Clofibrate and Mortality

MORTALITY MORTALITY

ITTITT 18.0%18.0% 19.5%19.5%

Compliers with ClofibrateCompliers with Clofibrate 15.0%15.0% 24.6%24.6%

Compliers with PlaceboCompliers with Placebo 15.1%15.1% 28.2%28.2%

Multivariate analysesMultivariate analyses 16.4%16.4% 25.8%25.8%(controlling for 40 confounders)(controlling for 40 confounders)

META-ANALYSISMETA-ANALYSIS

• Should be considered more as hypothesis formulating than as Should be considered more as hypothesis formulating than as hypothesis testinghypothesis testing

• May provide the best estimate of effect that should be tested a May provide the best estimate of effect that should be tested a priori in a large scale randomized trial designed to test the priori in a large scale randomized trial designed to test the questionquestion

• Utility is dependent on the quality and comparability of the data Utility is dependent on the quality and comparability of the data from its component trials.from its component trials.

• Will reduce the role of chance but may introduce bias and Will reduce the role of chance but may introduce bias and confoundingconfounding

Hennekens CH, DeMets D: The need for large scale randomized evidence Hennekens CH, DeMets D: The need for large scale randomized evidence without undue emphasis on small trials, their meta-analyses or subgroup without undue emphasis on small trials, their meta-analyses or subgroup analyses JAMA 2009;302:2361-2362.analyses JAMA 2009;302:2361-2362.

Meta-analysis is to analysis as meta-physics isMeta-analysis is to analysis as meta-physics is

to physics to physics

Professor William P. CastelliProfessor William P. Castelli

CAUSE AND EFFECT RELATIONSHIPSCAUSE AND EFFECT RELATIONSHIPS

A judgment based on the totality of evidence A judgment based on the totality of evidence which includeswhich includes

• Strength of associationStrength of association

• Consistency of findingsConsistency of findings

• Biological credibilityBiological credibility

• Temporal sequenceTemporal sequence

• Dose-response Dose-response

THE NEED FOR LARGE SCALE THE NEED FOR LARGE SCALE RANDOMIZED TRIALS TO PROVIDE A RANDOMIZED TRIALS TO PROVIDE A SUFFICIENT TOTALITY OF EVIDENCESUFFICIENT TOTALITY OF EVIDENCE

• Calcium channel blockers and risk of myocardial Calcium channel blockers and risk of myocardial infarctioninfarction

• Antioxidant vitamins and risks of cardiovascular Antioxidant vitamins and risks of cardiovascular disease and cancerdisease and cancer

• Cyclooxygenase-2 inhibitors and risks of Cyclooxygenase-2 inhibitors and risks of cardiovascular diseasecardiovascular disease

• Rosiglitazone and risk of myocardial infarctionRosiglitazone and risk of myocardial infarction

• Ezetimibe and risk of cardiovascular diseaseEzetimibe and risk of cardiovascular disease

Numbers of Randomized Patients in Completed Numbers of Randomized Patients in Completed Trials of Lipid Modifying Drugs on Clinical Trials of Lipid Modifying Drugs on Clinical

Cardiovascular Disease OutcomesCardiovascular Disease Outcomes

• StatinsStatins 90,056 90,056

• Nicotinic AcidNicotinic Acid 2,835 2,835

• Omega-3-FAOmega-3-FA 11,324 11,324

• FibratesFibrates– GemfibrozilGemfibrozil 2,531 2,531– FenofibrateFenofibrate 9,795 9,795

• EzetimibeEzetimibe 0 0

French FriesFrench Fries

How to burn* 400 calories: 

Walk 2 hour 20 minutes

20 years ago20 years ago TodayToday

210 calories

2.4 ounces How many calories are in these fries?610 calories6.9 ounces

Calorie difference: 400 Calories

*Based on 130-pound person.

Darwinism and Risk Darwinism and Risk of Cardiovascular Diseaseof Cardiovascular Disease

Walking the DogWalking the Dog

The United States is the fattest society in the The United States is the fattest society in the world and likely to be the fattest in the history world and likely to be the fattest in the history of the world.of the world.

Professor Charles H. HennekensProfessor Charles H. Hennekens

New York TimesNew York Times

A bit of cultural news …..A bit of cultural news …..

After a 2 year loanto the United States, David returns to Italy

Proud Sponsors

Established Risk Factors for CHDEstablished Risk Factors for CHD

Blood cholesterolBlood cholesterol10% 10% = 20%-30% = 20%-30% in CHD in CHD

High blood pressureHigh blood pressure5-6 mm Hg 5-6 mm Hg = 42% = 42% in Stroke in Stroke

= 16% = 16% in CHD in CHD

Cigarette smokingCigarette smokingCessation = 50%-70% Cessation = 50%-70% in CHD in CHD

Body weightBody weight BMI<25 vs BMI>27 = 35%-55% BMI<25 vs BMI>27 = 35%-55% in CHD in CHD

Physical activityPhysical activity20-minute brisk walk daily = 35%-55% 20-minute brisk walk daily = 35%-55% in CHD in CHD

““We must all hang together, or assuredly We must all hang together, or assuredly we shall all hang separately.”we shall all hang separately.”

– – Benjamin FranklinBenjamin FranklinJuly 4, 1776July 4, 1776

GOALS OF HEALTH CARE GOALS OF HEALTH CARE PROVIDERS AND ACADEMIC PROVIDERS AND ACADEMIC

RESEARCHERS RESEARCHERS Maximize benefit and minimize risk which is not to be confused with avoidance Maximize benefit and minimize risk which is not to be confused with avoidance

of risk.of risk.

Make clinical decisions based on the totality of evidence not dependence on Make clinical decisions based on the totality of evidence not dependence on particular subgroups of particular studiesparticular subgroups of particular studies..

Avoid misstatements of benefit to risk ratios which may increase publicity, Avoid misstatements of benefit to risk ratios which may increase publicity, academic promotions and grant support in the short run but confuse colleagues academic promotions and grant support in the short run but confuse colleagues and frighten patients and make it more difficult to conduct high quality research and frighten patients and make it more difficult to conduct high quality research

( COX-2 inhibitors and glitazones)( COX-2 inhibitors and glitazones)

When the totality of evidence is incomplete it is When the totality of evidence is incomplete it is appropriate to remain uncertain.appropriate to remain uncertain.

Hennekens CH, DeMets D: Hennekens CH, DeMets D:

The need for large scale randomized evidence without undue emphasis on small The need for large scale randomized evidence without undue emphasis on small trials, their meta-analyses or subgroup analyses JAMA 2009; 302:2361-2362.trials, their meta-analyses or subgroup analyses JAMA 2009; 302:2361-2362.