1. Biostatistics Case Studies 2015 Youngju Pak, PhD. Biostatistician ypak@labiomed.org Session 3: Research Study Designs I

2. Type of Research Study Designs  Observational Study : Researchers do not attempt to influence subjects or surroundings. The goal is to OBSERVE/COLLECT data on characteristic of interests w/o influencing subjects  Experimental Study : Researchers deliberately influence the course of events & investigate the effect of the treatment on selected population of subjects

3. More specific types of observational studies  Observation Studies  Ecological Studies : Utilize population level data.  e.g. Total cigarette consumptions and lung cancer prevalence by different countries  Case Reports / Case Series  Single subject or case  Simple description of series of individual case  e.g., CDC and prevention Morbidity and Mortality Week Reports(MMWR) of Pneumocystis pneumonia in previously healthy, homosexual men (LA,1981) ( http://www.cdc.gov/mmwr/preview/mmwrhtml/june_5.htm)

4. More specific types of observational studies cont.  Cross Sectional: Single time point studies that define a population at a specific time point, may unsuitable for rare disease  Prevalence or Incidence of disease or other characteristics  National Health and Nutrition Examination Survey on overweight and obesity in US.  Case-Control  Typically retrospective studies  Good for rare disease  Case/Control are collected by PI and retrospectively looking for risk factors/exposure  Prospective Longitudinal Cohort Study  Suitable for rare exposure  Large sample size are needed for rare disease  Risk factors/exposure are collected by PI and follow up study participants over time

5. How to make a better cross –Sectional Study  Sometimes it is hard to define denominator if it is an incidence study  Determining what to be studied is the most important things.  A disease or a disease condition or characteristics may be very difficult to define at a certain time point. eg, atherosclerosis is so common and its manifestations at time can be very subtle.  The definition of the condition and health characteristics under study SHOULD be standardized, reproducible, and feasible to apply for a larger scale study.

6. Advantage and Disadvantages of Cross-Sectional studies  Can avoid potential biases if it is truly population based sample  Short duration, less expensive for common diseases for a particular target population (e.g., workers in a given industry)  More expensive and time consuming compared with case-control studies particularly for rare diseases  Unsuitable for rare disease or for diseases of short duration (eg., influenza)  Potential bias due to non-responses (<80%)  Prevalence estimates are best derived from cross- sectional studies but factors associated with a disease or condition can be assessed by both cross-sectional and case-control studies.  Information you will need –Equivalence Margin Non-Inferiority Margin(NIM) =1.5 for the IOP study –Assumed mean difference in change of IOP between two groups -> usually zero difference assumed but it is assumed 0.5 for the IOP study –SD of changes of IOP = 3.5 –α (usually set to 2.5%) since the confidence level of the confidence interval is (100-2 x α) %

7. Cross Sectional Examples  Jonas JB, et al. Diabetes mellitus in rural India.Epidemiology. 2010;21:754–755.  Hedley AA, Ogden CL, Johnson CL, Carroll MD, Curtin LR, Flegal KM. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999-2002. JAMA 2004;291:2847-50.  Measure height and weight in National Health and Nutrition Examination Survey (NHANES)  Flegal KM, Graubard BI, Williamson DF, Gail MH. Cause-specific excess deaths associated with underweight, overweight, and obesity. JAMA 2007;298:2028-37.

8. Case-Control Studies  Observations regarding possible associations between a single outcome (usually a disease) and one or more hypothesized risk factors or Exposures  Well suited for studying – Rare diseases – Diseases with long latency periods  Generally quicker and less expensive than cohort studies Non-exposed No Disease ExposedNon-exposed Expose d Disease

9. Advantage and Disadvantages of Case-Control studies  Suitable for rare disease & Unsuitable for rare exposure  Multiple etiological factors can be studied simultaneously  Less expensive and time consuming  Associations with risk factors are consistent with other types of study if assumptions are met.  Do not estimate prevalence nor incidence  Relative risk can be indirectly measured by the odds ratio if the disease is rare

10. How to make a better Case-Control study?  Cases  Represents all patients who developed disease  Standardized selection criteria from well defined population  Can be NESTED in a larger cohort  Where?  Case registries  Admission records  Pathology logs  High participation rate  Controls  Represent “healthy” population without disease  No perfect control group exists  Standardized selection criteria from well defined population  Where?  General population  Neighborhood  Families  Hospitals

11. How to make a better Case-Control study?  All observation made using the same methods for cases & controls (consistency)  To avoid selection bias  the same hospital or family control  Avoid interviewer or recall bias  standardize data collection methods, train the interviewers  Consider cost & accessibility  To minimize confounding  Matched controls for age, sex, or other risk factors that are NOT interests of the study

12. Analyses for Case Control Studies ExposurePresence of DiseaseTotal DiseaseNo Disease Presentaba+b Absentcdc+d Totala+cb+da+b+c+d Summarizing frequencies with a 2x2 Contingency Table  Odd Ratio ( [a/b]/[c/d]) is usually used to test the association.  When a & c are very small(rare disease), then OR ≈ RR  Chi-square or Fisher’s exact tests  If the risk factor (X) is continuous measure such as BMI, the a logistic regression model will be used to estimate OR as one unit change in X.

13. Prospective or Longitudinal Cohort Studies  Observations concerning associations between a given exposure and subsequent development of disease  Examine multiple outcomes for a single exposure  Directly calculate incidence of disease for each exposure group.

14. Concurrent vs. Non-concurrent Prospective Cohort Concurrent  Defined population is surveyed.  Identify group with supposed risk factor  Identify similar group without risk factor  Follow them forward in time  Compare incidence rates between groups Non-Concurrent  Define population with presence/absence of exposure ascertained in accurate, objective fashion in the PAST  Retrospective study since it is based on historical data  Surveyed in present: disease occurrence  Define incidence rates and compare between the two groups

15. Advantage and Disadvantages of Prospective or Longitudinal Cohort studies  More representative of cases than case- control (incidence)  Natural history of disease  Directly measure Relative Risk (RR)  Less bias than case-control  Firmly establish temporal relationship b/w exposure and disease but exposure must be IDENTIFIED and MEASURED at the initiation and should be followed during the study period.  Suitable for Rare exposure

16. Advantage and Disadvantages of Prospective or Longitudinal Cohort studies  Long follow-up and free-living population follow up is both difficult and expensive  Usually large scaled study  Extensive baseline data may need  Unsuitable for rare disease ( can have zero frequency in a 2x2 table if the sample size is not enough)  Still bias exists (eg., participant selection, exposure assessment, or loss to follow up)

17. How to make a better Prospective Cohort study Exposed and non-exposed should be representative and well defined. Non-exposed status should be maintained during the study period Disease outcomes should be well defined prior to study and no changes during the study period Standard criteria applied to both exposed and non-exposed. Minimize loss to follow-up (>80%)

18. Analyses for Longitudinal Cohort Studies  Calculate incidence for the study period in exposed, unexposed, and test using Chi square or Fisher’s exact test.  Measure association with relative risk (or odds ratio) & 95% confidence limits  Life-tables (another way to say “survival analysis”) for “Time to Event” data Regression models

19. Nested Case-Control studies  Select from prospective cohort study eg., Stored samples  Use baseline and follow up samples and data from newly occurring cases  Compare to matched or unmatched controls  Efficient for expensive/difficult to measure  Helps avoid selection and data collection biases  Need to have enough cases in the cohort  Need to store all the samples and data

20. Nested Case-Cohort studies Similar to Nested Case-Control Controls come from a subcohort sampled from the entire cohorts at baseline(t 0 ), while controls for nested case-control are sampled from individuals at risk at the times(t 1 ) when cases are identified. Typically done when –Failure or event of interest is rare –Enormous resources to ascertain covariates values Very difficult to analyze

21. Nested Case-Control vs Nested Case Cohort Example :

22. Prospective Cohort : Example Cancer incidence for 10% of US population in1973

23. Methods SEER – Register cancer incidence for 10% of the US population in 1973 –Current incidence about 26% of the US population as of 2005 Analyze registered breast cancer patients at age of 20- 79 w/o previous cancer registered until Jan 1, 2002 from SEER. Exclude: women with bilateral breast cancer & found at autopsy or the death certificate Exposure: Irradiation from radiotherapy Disease outcomes: Cause specific mortality –Primary : Death from Heart Disease: acute myocardial infraction, other ischaemic heart disease or other heart disease ( using ICD 9 code) –Secondary: Death from Lung Cancer

24. Results

26. Nested Case-Control: Example Risk Factors for Deep Vein Thrombosis and Pulmonary Embolism A population-Based Case-Control Study John A,Heit, MD; Marc D, Sliverstein, MD; etc, JAMA Internal Medicine 2000;160:809-815  Deep Vein Thrombosis(DVT) occurs when a blood clot (thrombus) forms in one or more of the deep veins in your body. Deep vein thrombosis is a serious condition because blood clots in your veins can break loose, travel through your bloodstream and lodge in your lungs, blocking blood flow (pulmonary embolism). (resource: mayo clinic).  Venous Thromboembolism : Deep Venous Thrombosis & Pulmonary Embolism  Prevalence of DVT in US: new cases ( < 5 per 100,000 persons < 15 to 0.5% at age of 80 years. In general, 0.1%). Among these, 6% to 32% have PE based on severity of DVT.

27. Review points Where case & control are obtained? Are they consistent ? How were cases & controls defined? Selection criteria? Exclusion criteria? Why? Any potential bias? Minimize potential confounding?

28. Reference book