Lecture 9: Retrospective cohort studies and nested designs Jeffrey E. Korte, PhD BMTRY 747: Foundations of Epidemiology II Department of Public Health Sciences Medical University of South Carolina Spring 2015

Why do these kinds of studies? Retain advantages of prospective cohort study (e.g. exposure measured before disease occurs) Eliminate disadvantages of prospective cohort study (e.g. high cost, long time commitment) e.g. study of cancer with 15-20 year latent period

Retrospective cohort study Identify cohort of individuals based on their characteristics in the past Reconstruct their subsequent disease experience up to some defined time point in the more recent past, or up to the present (or into the future) This involves tracking them down and finding out what happened to them

Retrospective cohort study Examples: Studies of Workers (asbestos, benzene) College students (future risk of CHD predicted by participation in college sports; future risk of back pain predicted by spinal curvature) Patients (future risk of hysterectomy predicted by tubal sterilization; future risk of cancer predicted by DES exposure during pregnancy)

Should I do a retrospective cohort study or a case-control study? Participants identified on the basis of exposure Therefore may be the only option in the case of a rare exposure Must have good quality historical exposure data Case-control study Participants chosen on the basis of disease Therefore may be the only option in the case of a rare disease May be the only option if no information is available on past exposures

Retrospective cohort study Choosing participants Must have large % exposed to agent of interest Some must have high enough exposures to expect a detectable excess risk of disease Exposure data must be reasonably accurate Appropriate comparison group must be identifiable

Retrospective cohort study Measuring exposure Occupational studies: can use proxies for dose (length of employment) to assess dose-response Can sometimes impute exposure dose by synthesizing data sources: e.g. study of fluoroscopic radiation of the chest for tuberculosis in relation to breast cancer: collect number of procedures from patient or medical records; obtain procedure dose, body positioning, etc. from technicians; estimate radiation dose for each procedure

Retrospective cohort study Measuring disease Death certificates Disease registries (may allow analysis of incidence as well as mortality) Likely to underascertain disease occurrence If disease is underascertained in exposed group, but risk is compared to accurate population rates, then true risk factors may appear null or even protective

Retrospective cohort study Measuring confounders Often not possible But: keep in mind that not all risk factors are confounders (must be related to both exposure and disease in order to be a confounder) Can contact surviving cohort members to ascertain confounders or other information of interest Compare distribution between exposed/unexposed survivors Assess likelihood of confounding in full cohort

Retrospective cohort study Follow-up Individualized tracing methods required (in contrast to most prospective cohort studies) National Death Index Credit bureaus, state DMV, etc. City directories Contact relatives

Nested case-control study Useful when: Contemplating an expensive lab test Have frozen stored biologic samples from prospective cohort Select cases and (matched) controls from cohort; test only their samples Save enormous sums of money

Nested case-control study

Nested case-control study If sufficient number of cases has accrued: Select controls from unaffected cohort members who are still at risk and under surveillance at the time the cases develop disease May match controls on age, gender, time of entry into the study (in addition to length of follow-up) Controls may later serve as cases in analysis

Nested case-control study Example: Epstein-Barr virus and Hodgkin’s disease (Mueller et al 1989) Cohort of 240,000: stored blood in serum banks Cases identified through cancer registries and hospital records Controls matched on serum bank, gender, race, date of index serum (+/- 6 months), date of birth (+/- 1 year) Sera tested for antibody patterns to EBV and cytomegalovirus Results: EBV antibodies predict Hodgkin’s; antibody changes detectable 3-5 years prior to disease

Nested case-control study Relevant for designs other than stored blood: e.g. study of EMF and brain tumors/leukemia (Tynes et al 1994) Cohort of 13,300 railway workers 39 cases of brain tumor; 52 cases of leukemia 4-5 age-matched controls for each case Case-control design was beneficial, because the determination of exposure to electromagnetic fields was time-consuming and expensive for each participant

Case-cohort study Also called case-base study All cases identified from cohort Controls are a random sample of cohort at baseline Use a form of Cox model to compare each case to the subset of controls still at risk Controls are not matched on follow-up time, or other factors (age, sex, etc.) These factors must be accounted for in analysis

Case-cohort study

Case-cohort study Can be used to obtain rate ratio, risk ratio, and odds ratio estimates within a cohort Can compare rate and risk estimates between exposed groups within cohort versus an external population e.g. risk of disease in exposed can be compared to risk in unexposed; can also be compared to risk in general population

Should I do a case-cohort study or a nested case-control study? Advantages of nested case-control: Matching on time (more statistically efficient, unless everyone joins the study at the same time and has the same follow-up) Analysis is similar to case-control study Easier to calculate sample size Does not require control disease ascertainment beyond the time of case data collection

Should I do a case-cohort study or a nested case-control study? Advantages of case-cohort Can use same control group for multiple case groups, and for unanticipated future studies Flexible analysis in choice of time scale (no matching on cohort entry or follow-up time) Quicker and easier to select controls Subcohort represents population; can estimate risks of various things

Analysis overview Nested case-control study: analyzed as case-control study Conditional logistic regression (matched on follow-up time, perhaps other factors Case-cohort study: analyzed as cohort study Cox proportional hazards models for time-to-event data Poisson for rare event/count data Log binomial to estimate relative risk