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Cohort design
- 1. Cohort Studies Amita Kashyap Professor and Head (Com. Medicine) SMS Medical College, Jaipur
- 2. Study Designs to elucidate etiologic or causal relationships âŚâŚ 1. First, we determine whether there is an association between a factor or a characteristic and the development of a disease by studying the characteristics of groups/individuals, or both. 2. Second, we derive appropriate inferences regarding a possible causal relationship from the patterns of association that have been found.
- 3. Learning Objectives ⢠To describe the designs of cohort studies and options for the conduct of longitudinal studies. ⢠To illustrate the cohort study design with important historical examples. ⢠To discuss some potential biases in cohort studies.
- 4. Cohort Study â patient profile ⢠A 28 yrs old primigravida, DEVELOPED raised B.P. during an otherwise uncomplicated pregnancy. ⢠Lobor was induced bcz the pregnancy was overdue by 2 wks. ⢠During labor- fetal distress was seen (Obstetrician noted thick greenish fluid containing meconium) ⢠At the time of delivery baby was limp & cynotic, had no spontaneous respiration, HR was 50 beats/ min.
- 5. Cohort Study â patient profile CTD⌠â˘Baby showed no grimace on suction of meconium from his mouth and nose. ⢠Despite vigorous resuscitation using Bag and Mask ventilation with 100% O2 and chest compression, Apgar score didnât improve much (at 1 min of life it was 1 and became 2 after 5 min with 110 beats/min HR and 3 after 10 min resuscitation) hence admitted in ICU â˘After 12 days of care in ICU he was discharged without any neurological deficit. â˘No history of seizure in first 24 hour
- 6. Continued⌠⢠Parents of this child would like to know â â will their son develop Normal Mental Capacity? â Will he have Physical Disabilities? etc.. ⢠Doctor can use his experience or read othersâ âŚ.most definitive will be RTCâŚexpose randomly a group of new born to asphyxia and compare their growth and development with control groupâŚâŚ.BUT we cannot do this!!!! ⢠The observational Study Design which is most similar to Clinical Trial is Cohort Study Design
- 7. Cohort Study- Prospective Design Cohort Selected for study Subjects Exposed (with asphyxia; very low Apgar score ďŁ3) Subjects Un-exposed (without asphyxia; higher Apgar score ďł8) With outcome; disabled Without outcome; Not disabled With outcome; Without outcome; Not disabled Onset Time Direction of enquiry Question is â âwhat will happen?â New born Btw July to Decâ89 disabled Outcome in 2001
- 8. Cohort Study on Utility of Apgar Score USA ⢠Study enrolled 49,000 infants whose scores were recorded at 1 and 5 min of age. If the score was < 8 at 5 min, it was recorded at 10,15 and 20 min. ⢠All children were followed for 7 years. ⢠The occurrence of seizure was recorded by observation in nursery and histories at the interval of 4, 8, 12 and 18 months of age, and yearly thereafter. ⢠Cerebral palsy determined by PE at 7 yrs of age. ⢠A psychological and developmental assessment was also done at 7 yrs
- 9. Cohort Study on Utility of Apgar Score USA ⢠12 out of the 99 children who survived and had apgar score 0-3 at 10, 15 or 20 min, developed cerebral palsy (probability of getting cerebral palsy = 12%) ⢠Ten of these 12 children (83%) had seizers in first 24 hrs of life. ⢠11 of these 12 (92%) also had delayed milestones. ⢠80% of the children who survived and had Apgar Score 0-3 at 10 min or later, were free from any major handicap at early school. ⢠The study presents a range of experience which no professional can accumulate in a life time!
- 10. Cohort Study â Retrospective Design Cohort Selected for study Subjects Exposed (with asphyxia; very low Apgar score <3) Subjects Un-exposed (without asphyxia; higher Apgar scoreďł8) With outcome; disabled Without outcome; Not disabled With outcome; Without outcome; Not disabled Onset 2001 Time Direction of enquiry Question is â âwhat will happen?â New born disabled APGAR Score 1989 Records
- 11. Design of a Cohort Study ⢠We begin with an exposed group (a + b) and an unexposed group (c + d). ⢠Of the (a + b) exposed persons, the disease develops in a but not in b. â Thus the incidence of the disease among the exposed is a / a+b . Similarly, ⢠of the (c + d) unexposed persons in the study, the disease develops in c but not in d. â Thus the incidence of the disease among the unexposed is c / c + d .
- 12. A Hypothetical Cohort Study of Smoking and Coronary Heart Disease Then Follow to see whether First Select CHD Develops CHD doesnât Develops Total Incidence per 1,000 per year Smoke cigarettes 84 (a) 2,916 (b) 3,000 (a+b) 28.0 Do not Smoke cigarettes 87 (c) 4,913 (d) 5,000 (c+d) 17.4 (c+d) (c) (a+b) (a)
- 13. Basic Methods to Select Cohort: 1. On the basis of Exposure occupationally exposed cohorts compared with similarly aged community residents who do not work in those occupations. 2. On the basis of some factor not related to exposure such as community of residence â Framingham town in Massachusetts, approximately 20 miles west of Boston . 3. Using the results of the histories or the tests, one can separate the population into exposed and unexposed groups (or those who have and those who do not have certain biologic characteristics).
- 14. Selection of subjects ⢠Both exposed and unexposed groups must be:â a) free of the outcome of interest at the start of the study b) Eligible to develop the outcome of interest during the course of the study ⢠Selection of subjects is influenced by :â a) Type of exposure b) Level or Frequency of exposure c) Accessibility and likelihood of continuing
- 15. Exposed Group a) Type of exposure I. Common exposures- e.g. gestational diabetes or hypertension; a general population of pregnant women can be used to construct the cohort II. Rare/ Specific exposures- like in-vitro fertilizationâs as a RF for developmental disability in off-springs; pregnant women from Infertility clinics are included in cohort b) Frequency of exposure- I. Can be dichotomous (Apgar score 0-3 and >3)or Graded (Apgar score 0-3, 4-6, 7-10) or continuous c) Accessibility and likelihood of continuing I. Medical records, Nurses, students, doctors etc
- 16. Unexposed For Exposed For both Unexposed subjects should be selected from the same (or comparable) source population as the exposed group The baseline characteristics of exposed persons should not differ systematically from unexposed persons, except for the exposure of interest both exposed and Unexposed persons should be free but equally susceptible to develop the disease of interest at the beginning Multiple comparison groups of unexposed persons chosen may reinforce validity of findings Equivalent information (quantity and quality) on exposure and outcome for both groups Both groups should be accessible for follow-up Guidelines for selection of Exposed and Unexposed subjects in Cohort Study
- 17. Exposure ⢠Define clearly I. Acute; one time episode e.g. birth asphyxia II. Long-term continuous or intermittent ⢠Once selected as per inclusion criteria, should not subsequently be excluded from the analysis bcz of change in exposure status during follow up â frequent reassessment of exposure and outcome status may be required if exposure changes over time ⢠Source of information â if medical records!! ⢠Measurement of exposure â Objective vs Subjective
- 18. Clinical Response ⢠It is imperative that subjects are free from outcome at the beginning ⢠A standard diagnostic protocol to be followed â regardless of exposure ⢠Methods of data collection â â Short term outcome like perinatal deaths after birth asphyxia are easy to assess but â to assess neurological and developmental defects at least 7 year follow-up is required!!! ⢠Assessor should be blind of exposure status for accuracy and reliability of outcome
- 19. Example Relationship btw 10 min Apgar Score & Risk of death in first yr of life among infants weighing >2500g
- 20. Analysis Outcome Exposed Apgar Score 0-3 Unexposed Apgar Score 4-6 Total Death A (42) B (43) A+B (85) No Death C (80) D (302) C+D (382) Total A+C (122) B+D (345) A+B+C+D Risk of death among Exposed = No. of Exposed who die, (42) Total No. of Exposed (122) Risk of death among Unexposed = No. of Unexposed who die, (43) Total No. of Unexposed , (345) Risk Ratio= R(exposed) R(Unexposed) = 0.344 = 34.4% = 12.5% = 34.4/ 12.5 = 2.8
- 21. Inference â Babies weighing >2500g with very low 10 min Apgar Score are Aproximately 3 times more likely to die in first year of life than babies with similar weight but moderate Apgar Score
- 22. 0-3 4-6 7-10 10 minute Apgar Score 1 2 3 Risk Ratio An argument that the linkage btw Apgar score and Death in the first year of life is one of the cause and effect, can be strengthen it by a dose response relationship, A third group of new born with 7-10 Apgar score is therefore included in the study. 2.8 1.4 0.15
- 23. Other measures of Risk Association Risk difference or excess Risk = R(exposed) - R (Unexposed) =( A/A+C) â (B/ B+D) = (42 / 122) â (43 / 345) = 0.344 â 0.125 = 0.219 i.e. risk of death in the first year of life is 21.9% more in children with Apgar score 0-3 then 4-6. Attributable Risk Percent = {R(exposed) - R (Unexposed)} Outcome Exposed Apgar Score 0-3 Unexposed Apgar Score 4-6 Total Death A (42) B (43) A+B (85) No Death C (80) D (302) C+D (382) Total A+C (122) B+D (345) A+B+C+D R(exposed) X100 ARP = 0.344 â 0.125 / 0.344 X 100 = 63% ARP is used as an indicator of the public health impact of exposure
- 24. Rate Ratio ⢠In cohort study we can calculate rate of occurrence of outcome e.g. Death Rate in CVD & Cholesterol level Exposed Persons Cholesterol Level 201-240mg/dl Unexposed Persons Cholesterol Level ďŁ197mg/dl Total No. of Outcomes (Death) A (26) B (14) A+B (40) Person Time PT (exposed) 36,581 PT (Unexposed) 68,239 PT (Total) 104,820 Rate Ratio = Rate of outcome among exposed / Rate of outcome among unexposed A/ PT (exposed) B/ PT (Unexposed) = 26/ 36,581 14/ 68,239 = = 3.5 3.5 times higher mortality in persons with borderline high cholesterol Than that of Lower cholesterol levels
- 25. The framingham study Started in 1948 ⢠Small Town with stable (migration out was low) population of just less than 30,000 residents, was appropriate for such a study (easy to follow) ⢠Residents were considered eligible if they were between 30 and 62 years of age at study initiation and were free of cardiovascular disease at that time.
- 26. The framingham study Started in 1948 ⢠suggested âexposuresâ were defined, including age and gender, smoking, weight, blood pressure, cholesterol levels, physical activity, and other factors. ⢠New coronary events (incidence) were identified by examining the study population every 2 years and by daily surveillance of hospitalizations at the only hospital in Framingham.
- 27. The framingham study Started in 1948 ⢠It permitted the investigators to study multiple âexposures,â such as hypertension, smoking, obesity, cholesterol levels, and other factors, as well as the complex interactions among the exposures, by using multivariable techniques. ⢠Thus, a cohort study that begins with an exposed and an unexposed group focuses often on only one specific exposure, while a cohort study that begins with a defined population can explore the roles of many exposures to the study outcome measure(s).
- 28. Potential Biases in Cohort Studies Selection biases â ⢠Nonparticipation- if those who refuse to join a study are more likely to smoke than those who consent to participate!!!! ⢠Nonresponse - If people with the disease are selectively lost to follow-up, and those lost to follow-up differ from those not lost to follow- up, the incidence rates calculated in the exposed and unexposed groups will clearly be difficult to interpret.
- 29. Information biases ⢠If the quality and extent of information obtained is different for exposed persons than for the unexposed persons- in historical cohort studies ⢠If the person who decides whether the disease has developed in each subject also knows whether that subject was exposed, and if that person is aware of the hypothesis being tested, that personâs judgment as to whether the disease developed may be biased by that knowledge. â This problem can be addressed by âmaskingâ ⢠As in any study, if the epidemiologists and statisticians who are analyzing the data have strong preconceptions, they may unintentionally introduce their biases into their data analyses and into their interpretation of the study findings.
Editor's Notes
- a cohort study is indicated when good evidence suggests an association of a disease with a certain exposure or exposures (evidence obtained from either clinical observations or case-control or other types of studies). Often, we collect biologic specimens at study baseline (enrollment), allowing testing of these samples in the future, often when new test methods are developed and/or new hypotheses are generated. As an example, George Comstock collected serum specimens at the time of a community assessment in the 1960s in Washington County, Maryland. Decades later, these specimens were tested for âcluesâ to the development of cancer. Results from the Campaign Against Cancer and Heart Disease (CLUE II) cohort study that Dr. Comstock founded showed that high serum cholesterol increases the risk of high-grade prostate cancer and subsequently supports the hypothesis that cholesterol lowering is a potential mechanism by which statins, a cholesterol-lowering medications, could have anticancer effects Because cohort studies often involve follow-up of populations over a long period, cohort approach is particularly attractive when we can minimize attrition (losses to follow-up) of the study population. Consequently, such studies are generally easier to conduct when the interval between the exposure and the development of disease is short. An example of an association in which the interval between exposure and outcome is short is the relationship between rubella infection during pregnancy and the development of congenital malformations in the offspring.
- A pediatrician attended the delivery of a newborn. the mother, a 28 yrs old primigravida, had experienced elevated B.P. during an otherwise uncomplicated pregnancy. Perinatal asphyxia can be defined as fetal hypoxia during labor/delivery. It is the major cause of perinatal death and impaired development and neurological functions among survivors. Causes of perinatal asphyxia are not completely understood, but a number of factors are associated like â preeclampsia/ eclampsia, hypotension in pregnancy, placental insufficiency, and prematurityâŚ.leads to inadequate oxygenationâŚ.leads to acidosis as tissues resort to anaerobic glycolysis for energy productionâŚ.leads to cellular injury in brainâŚâŚwhich can manifest as death, cerebral palsy, mental retardation and seizers Studies in primates have shown that asphyxia of >25min is required for brain cell injury and usually this much asphyxia leads to death If parents of this child wants to know the future life complications âŚlike his intelligence etc..doctor has to know for sure his probabilities before telling them.. He can use his experience or read othersâ âŚ.most definitive will be RTCâŚexpose randomly a group of new born to asphyxia and compare their growth and development with control groupâŚâŚ.BUT we cannot do this!!!! So can resort to observe natural cohort of such children and compare them with normal cohort..
- Apgar Score â 0 1 2 Heart Rate Abscent <100 >100 Resp Abscent Slow. Irregular Regular, crying Muscle Tone Limp Slow flexion Active motor Color Blue/Pale body pink extremities blue completely pink Reflex Response None Grimace cough, sneez to cathetyer in nostril
- In a cohort study information about the risk factor (exposure) is determined prior to observation of the disease. A large study conducted in USA on the utility of Apgar score enroled 49000 infants whose scores were recorded at 1 and 5 min of age. For those infants who did not achieve a score of 8 or higher at 5 min, apgar scores recorded at 10,15 and 20 min. All children were followed for 7 years. The occurrence of seizure was recorded by observation in nursery and histories at the interval of 4, 8, 12 and 18 months of age, and yearly thereafter. Cerebral palsy determined by physical examination at 7 yrs. A psychological and developmental assessment was also done at 7 yrs This study demonstrated that low Agar scores are risk factor for cerebral palsy. However 55% of the children with cerebral palsy at age 7 had apgar scores of ďł7 at 1min and 73% scored ďł7 at 5min. of the 99 children who survived and had apgar score 0-3 at 10, 15 or 20 min, 12 had cerebral palsy (12/99=12.12 i.e. probability of getting cerebral palsy) and 11/12 also had delayed milestones. Ten of these children 83% had seizers in first 24 hrs of life. Of the children who survived and had apgar score 0-3 at 10 min or later, 80% were free from any major handicap at early school. This study provides information required by the pediatrician to discuss with parents of the new born in question. The study presents a range of experience which no professional can accumulate in a life time! So the pediatrician now can tell parents that though their baby does have an increased risk of crebral palsy and developmental delay, such an outcome occurs in only about 1 in 8 (12%)asphyxiated neonates. Because the baby did not have a seizure in the first 24 hrs of life, the prognosis may be more favorable. It should be reassuring to the parents to learn that 80% of even the most severely asphyxiated newborns were free of major neurologic handicap at early school age. Framingham heart studyâŚ.. Beginning in 1950, a sample of 6500 individuals aged 30-59 yrs was chosen from approx. 10,000 populationapprox. 5100 individuals with no h/o atherosclerotic CVD aggreed to participate. Each individual was examined at the beginning of the study and then every 2 yrs there after
- In a cohort study information about the risk factor (exposure) is determined prior to observation of the disease.
- This study demonstrated that low Agar scores are risk factor for cerebral palsy. However 55% of the children with cerebral palsy at age 7 had apgar scores of ďł7 at 1min and 73% scored ďł7 at 5min. of the 99 children who survived and had apgar score 0-3 at 10, 15 or 20 min, 12 had cerebral palsy (12/99=12.12 i.e. probability of getting cerebral palsy) and 11/12 also had delayed milestones. Ten of these children 83% had seizers in first 24 hrs of life. Of the children who survived and had apgar score 0-3 at 10 min or later, 80% were free from any major handicap at early school. probability of getting cerebral palsy12/99*100 =12.12% This study provided information required by the pediatrician to discuss with parents of the new born in question.
- Retrospective cohort is good for exposures which are not present now but had occurred in past///require good records. If outcome is rare the required sample size would be too large but if exposure is rare it can be a study with great power bcz it allows selective inclusion of exposed persons Long follow up can lead to many problems like âŚdrop out, death, or non participation, change of occupationâŚleft smoking âŚ. If loss to follow up is substantial it affects validity (if lost individuals differ in outcome from those who remained)
- The use of these calculations is seen in a hypothetical example of a cohort study shown in Table 8.2. In this cohort study, the association of smoking with coronary heart disease (CHD) is investigated by selecting for study a group of 3,000 smokers (exposed) and a group of 5,000 nonsmokers (unexposed), all of whom are free of heart disease at baseline. Both groups are followed for the development of CHD, and the incidence of CHD in both groups is compared. CHD develops in 84 of the smokers and in 87 of the nonsmokers. The result is an incidence of CHD of 28.0/1,000 in the smokers and 17.4/1,000 in the nonsmokers. Note that because we are identifying new (incident) cases of disease as they occur, we can determine whether a temporal relationship exists between the exposure and the disease (i.e., whether the exposure preceded the onset of the disease). Clearly, such a temporal relationship must be established if we are to consider the exposure a possible cause of the disease in question.
- Cohort studies, in which we wait for an outcome to develop in a population, often require a long follow-up period, lasting until enough events (outcomes) have occurred. When the second approach is usedâin which a population is identified for study based on some characteristic unrelated to the exposure in questionâthe exposure of interest may not take place for some time, even for many years after the population has been defined. Consequently, the length of follow-up required is even greater with the second approach than it is with the first. Note that with either approach the cohort study design is fundamentally the same: we compare exposed and unexposed persons. This comparison is the hallmark of the cohort design. Types of Cohort Studies A major issue with the cohort design just described is that the study population often must be followed up for a long period to determine whether the outcome of interest develops. Consider as an example a hypothetical study of the relationship of smoking to lung cancer. We identify a population of elementary school students and follow them; 10 years later, when they are teenagers, we identify those who smoke and those who do not. We then follow both groupsâsmokers and nonsmokersâto see who develops lung cancer and who does not. Let us say that we begin our study in 2012 Let us suppose that many children who will become smokers will do so within 10 years. Exposure status (smoker or nonsmoker) will therefore be ascertained 10 years later, in the year 2022. For purposes of this example, let us assume that the average latent period from beginning smoking to development of lung disease is 20 years. Therefore development of lung cancer will be, on average, ascertained 20 years later, in 2042. prospective cohort study (also called by some a concurrent cohort or longitudinal study). It is concurrent (happening or done at the same time) because the investigator identifies the original population at the beginning of the study and, in effect, follows the subjects concurrently through calendar time until the point at which the disease develops or does not develop. What is the problem with this approach? The difficulty is that, as just described, the study will take at least 30 years to complete. Several problems can result. If one is fortunate enough to obtain a research grant, such funding is generally limited to a maximum of only 5 years. In addition, with a study of this length, there is the risk that the study subjects will outlive the investigator, or at least that the investigator may not survive to the end of the study. Given these issues, the Disease prospective cohort study often proves unattractive to investigators who are contemplating a new research question Do these problems mean that the cohort design is not practical? Is there any way to shorten the time period needed to conduct a cohort study? Let us consider an alternate approach using the cohort design (Fig. 8.6). Suppose that we again begin our study in 2012, but now we find that an old roster of elementary schoolchildren from 1982 is available in our community and that they had been surveyed in high school regarding their smoking habits in 1992. Using these data resources in 2012, we can begin to determine who in this population developed lung cancer and who has not. This is called a retrospective cohort or historical cohort study (also called a nonconcurrent prospective study). However, note that the study design does not differ from that of the prospective cohort designâwe are still comparing exposed and unexposed groups. What we have done in the retrospective cohort design is to use historical data so that we can telescope (reduce) the frame of calendar time for the study and obtain our results sooner. It is no longer a prospective design, because we are beginning the study with a preexisting population to reduce the duration of the study. However, as shown in Fig. 8.7, the designs for both the prospective cohort study and the retrospective or historical cohort study are identical: we are comparing exposed and unexposed populations. The only difference between them is calendar time. In a prospective cohort design, exposure and unexposure are ascertained as they occur during the study; the groups are then followed for several years into the future and incidence is measured. In a retrospective cohort design, exposure is ascertained from past records and the outcome (development or no development of disease) is determined when the study is begun. It is also possible to conduct a study that is a combination of prospective cohort and retrospective cohort designs. With this approach, exposure is ascertained from objective records in the past (as in a historical cohort study) and follow-up and measurement of outcome continue into the future.
- If the exposure can be categorized into multiple levels or gradations, the investigator can determine whether a relationship exists between the dose of the exposure and outcome (response). E.g. in our example the study may seek to determine whether the risk of neurological disability rises as the Apgar score decreases. If such a relationship exists, the assumption that perinatal asphyxia is a cause of neurological disability is strengthened.
- In the study of perinatal asphyxia unexposed group was defined as infants with higher Apgar scores(7-10). In framingham heart study , several RFs were of interest which were relatively prevalent in the population; so a representative sample was drawn from the population and people were subdivided into exposure group depending on the Rf of interest and followed up for the outcome. In cases of specific exposures like â in-vitro fertilizationâŚunexposed group selection is criticalâŚ.we have to take unexposed group from general obstetric clinics but if pregnant women there are systematically different on some parameter which affects the outcomeâŚthen comparison will not bring out actual effect of in-vitro fertilization on congenital malformations This problem illustrates why RCTs are better âŚwith randomization factors (both known and unknown) get balanced out in both the groups. This increases confidence that an observed association is in fact the result of the exposure. Exposed and unexposed should be from same time period (concurrent) otherwise other factors like availability of different level of medical care may spuriously affect outcome
- Once selected as per inclusion criteris should not subsequently be excluded from the analysis bcz of change in exposure status during follow up e.g. in a study to find out association of antiemetic given during pregnancy and spontaneous abortion, the medication may be discontinued due to spontaneous abortion!!! The potential for change in exposure status has important implication on frequency of follow ups --frequent reassessment of exposure and outcome status may be required if exposure changes over time Source of information â if medical records!!- e.g. if we take historical cohort in our perinatal asphyxia studyâŚ.Apgar scoring may be spurious (many a times it is done after everything is done to complete the paper work)
- Be sure that subjects donât have outcome at the beginning â we can remove those subjects from the study who develop outcome of interest early in the study Degree of surveillance should be similar in both exposed and unexposed group â
- Relative risk is a measure of strength of association btw exposure and outcome. A sense of the statistical precision of this estimated risk ratio can be obtained by calculating confidence interval around the point estimate of 2.8
- Attributable Risk Percent â risk differrence is expressed as percentage of the total risk experienced by the exposed group Almost two third (63%) of the total risk of infant mortality for new borns who weigh more than 2500g and had Apgar Score of 0 -3 is related to an Apgar score below 4-6 level. ARP is used as an indicator of the public health impact of exposure. These data suggest that birth asphyxia is a major contributor to â but not the sole cause of â infant mortality among severely asphyxiated children
- Since Null value 1 is excluded from 95% CI findings are statistically significant in other words, these data are not consistent with the null hypothesis of no association btw apgar score and infant mortality at the prescribed 95% level of confidence- an association as strong as observed cannot be explained just by chance An argument that the linkage btw Apgar score and death in the first year of life is one of cause and effect is strengthened if a dose response relationship can be demonstrated. A third group of new born with 7-10 Apgar score is therefore included in the study. Comparison of the risk of death in that group with the previous reference group, which had intermediate Apgar score of 4-6 yields a RR of 0.15 , with an approx. 95% CI of 0.11 to 0.21
- The rationale for using this age range was- that people younger than 30 years would generally be unlikely to manifest the cardiovascular end points being studied during the proposed 20-year follow-up period. Many persons older than 62 years would already have established coronary disease, and it would therefore not be rewarding to study persons in this age group for identifying the incidence of coronary disease. It consisted of 5,127 men and women who were between 30 and 62 years of age at the time of study entry and were free of cardiovascular disease at that time. In this study, many suggested âexposuresâ were defined, including age and gender, smoking, weight, blood pressure, cholesterol levels, physical activity, and other factors. New coronary events (incidence) were identified by examining the study population every 2 years and by daily surveillance of hospitalizations at the only hospital in Framingham.
- A major problem associated with long-term follow-up of large cohorts is that, by the time the cohort has been established and followed for a number of years, the hypotheses that originally led to the establishment of the cohort may no longer be of sufficient interest or relevance because scientific and health knowledge has changed over time. Furthermore, as new knowledge leads to new hypotheses and to questions that were not originally anticipated when the study was initiated, data on the variables needed to test such new hypotheses and to answer such new questions may not be available in the data originally collected. An example from HIV/ AIDS research illustrates these issues. In the early 1980s, when clusters of men were identified who had rare malignancies associated with compromised immune function, later to be defined as HIV/AIDS, the NIH launched the Multicenter AIDS Cohort Study in 1983 and enrolled the first participants in four US cities in 1984 The goal was to identify risk factors for this viral disease and to elucidate the natural history of the disease. With the advent of highly active antiretroviral therapy in 1996, virtually all of the study participants who were already infected were then placed on treatment, and their immune systems were reconstituted. How then could the natural history of a treated infection remain relevant? Was there any use in continuing to follow this cohort? Indeed, a vast number of new, relevant questions unfolded, chief among them has become what is the impact of long-term antiretroviral therapy treatments upon natural aging and the incidence of chronic diseases (cancer, cardiovascular disease, and diabetes, among others)? Furthermore, new genetic tests have been discovered over the past 15 years that provide new insights into why some participants do better than others on treatment. It must be emphasized that cohort studies whose participants are examined periodically, such as the Atherosclerosis Risk in Communities (ARIC) study,11 allow evaluation of new hypotheses based on information that is collected in follow-up examinations.