Hui JinSchool of Public Health, Southeast University

Prospective Cohort Studies

What is a Cohort?

• A “cohort” is a group of people who have something in common.

• Can represent the source population—the population from which cases of disease arise.

• Examples of cohorts:– All employees in an office building– Everyone who attended a football game– All the residents of a neighborhood

The basic fighting unit was a cohort, composed of six centuries (480 men plus 6 centurions). The legion itself was composed of ten cohorts, and the first cohort had many extra men—the clerks, engineers, and other specialists who did not usually fight—and the senior centurion of the legion, the primipilus, or “number one javelin.”

prospective cohort

cohortExposed

Not exposed

Sick

SickNot sick

Not sick

measure of exposure

Occurrence of disease

exposed – unexposed studyMeasure of exposureretro / prospective

Cohort Studies

• Tend to be retrospective (exposures in the past in relation to disease that has already happened).

• Occurrence of disease in exposed group compared to occurrence of disease in unexposed group = risk ratio.

• Risk ratio tells whether disease is associated with exposure and strength of association.

Identifying a Cohort

• To use a cohort study, you must identify every person in the cohort.– Possible when the group is small and well

defined (e.g., wedding reception, cruise ship, school, prison).

• Option to interview every member of the cohort or a sample of the cohort.

Identifying a Cohort

• Sometimes it may be difficult to define a suitable cohort.– Can you find every single person who ate at t

he Main Street Deli on January 10-20? – How would you locate every person buying an

d/or eating contaminated lunch meat from a local supermarket chain?

• An alternative: the case-control study.

Why Do A Cohort Study?

• Get incidence data

• Study a range of possible risk factors

• Establish temporal sequence

• Get representative data

• Prepare for randomized controlled trial

• Establish a research empire

Cohort Study DesignTypes of Cohorts

• Fixed Cohort – A group of individuals recruited and enrolled at a

uniform point in the natural history of a disease or by some defining event

– Cohort does not take on new members after it is assembled

– Examples• Patients admitted to the ER with acute MI• Survivors of Hiroshima bombings• Children born to HIV-infected mothers

Cohort Study DesignType of Cohorts

• Open cohort– A group of individuals recruited and enrolled

through a mechanism that allows for in and out migration of people

– Defined by characteristic other than disease, e.g., geographic location, administrative unit

–Dynamic population

– Examples• Framingham Study

Sources of Cohort Data

• Clinic Visits– Laboratory Assays– Interview– Physical Examination– Imaging – Physiologic tests

• Home visits• Mailed materials• Telephone Interview

• Medical Records• Administrative Data

– Medicare– Medicaid– Managed Care– Veterans Admin

• Birth Records• Death Certificates• Specimen Bank

Challenges in Cohort Studies• Possibly long duration

• Possibly large sample size

• Need to recruit people “at risk”

• Drop outs, Deaths, Other losses

• Concern about residual confounding

• Multiple comparisons Type I error

How to Exploit Cohort Design When Time is Short & Money is Scarce

• Analyze existing data from another study• Piggy-back onto on-going study• Choose hospital-based cohort• Choose short-term outcome• Consider administrative data• Consider public-use data• Consider non-concurrent design

Famous Cohort Studies

1. Population-based1. Cardiovascular

2. Child Health

3. Special Exposures

2. Non-Population based 1. Occupational – for convenience

2. Occupational – to study the occupation

3. Health care settings

4. Veterans

1. CARDIOVASCULAR DISEASE

• Framingham, MA 

• Tecumseh, MI 

• Evans county, GA (biracial)

• Muscatine, IA

• Bogalusa, LA (children)

The Framingham Study

• Began in 1948 for Cardiovascular disease

• A small town 20 miles from Boston in Massachusetts, USA

• Population under 30,000

• Participants between 30-62 years of age

• Follow up for 20 years

• Sample size of 5000

Other famous cohorts include; British Physicians Cohort UK; Nurses Health Study USA, Women Health Initiative (WHI), Study of women across the nation (SWAN) in USA

2. CHILD HEALTH • National Birthday Trust Studies

One week of births in England and Wales in 1946, 1958 and 1970

• Project on Premature InfantsAll births < 1,500 g or < 32 weeks in Holland in 1983

• The National Childrens Study http://www.nichd.nih.gov/about/despr/despr.htm

Will we shortly begin a study in the US of 100,000 pregnancies with offspring followed to age 21?

3. SPECIAL EXPOSURES • Atomic Bomb Casualty Commission (ABCC):

Hiroshima and Nagasaki survivors (effects of radiation)

• Dutch famine survivors (effects of starvation)

• Seveso (effects of dioxin exposure)

1. Occupation-based cohorts

because of convenient follow-up

• British Doctors Study (Doll – smoking)

• Nurses Study (Speizer, Willett – many issues)

• London civil servants (Marmot - SES)

• Taiwanese civil servants (Beasley – liver cancer)

Nurses Health Study

• Prospective data from the Nurses' Health Study, a large cohort study involving over 121,700 women, in 1976 from eleven states of USA; by mailing a questionnaire every two years provide a basis for a better understanding outcomes in women, including chronic diseases, cancer, and role of biological, demographic, hormonal, lifestyle, nutritional and other risk factors.

2. Occupation based to study exposures

• Benzene-workers (leukemia)

• Coke-oven workers (lung cancer)

• Asbestos workers (lung cancer)

• Radium dial painters (oral cancer)

Lancet. 1977 Jul 9;2(8028):76-8.Leukaemia in benzene workers.Infante PF, Rinsky RA, Wagoner JK, Young RJ.Abstract

Workers occupationally exposed to benzene in 1940-49 were followed for vital status up to 1975. In comparison with two control populations, a significant (P less than 0-002) excess of leukaemia was observed. These figures under-estimate the true leukaemia risk to benzene-exposed workers, because follow-up is only 75% complete and the untraced 25% of the study population were all regarded, in the statistical analysis, as being alive at the end of the study period. Existing records indicate that the benzene levels themselves were generally below the limits recommended at the time of their measurement.

3. Sampling from health care settings

• National Collaborative Perinatal Project:Almost all pregnancies at 12 medical centers 1959-1966 – N about 50,000. (causes of CP)

• Child Health and Development Studies:

Kaiser-Permanente births (many issues) • Patients treated with radiation for polycythemia or

ankylosing spondylitis (radiation and cancer)

• National Collaborative Perinatal Project:

http://www.archives.gov/research/electronic-records/nih.html

• The study was conducted by NIH's National Institute of Neurological Diseases and Stroke.

• The NCPP data constitute an important resource for biomedical and behavioral research in many areas of obstetrics, perinatology, pediatrics, and developmental psychology. There are 6,700 data items on the approximately 58,000 study pregnancies.

4. Veterans

• Mustard-gas poisoning from WW I (lung disease)

• Vietnam Veterans (post-traumatic stress disorder, agent orange effects)

• Gulf War Veterans (Gulf war syndrome)

http://www.millenniumcohort.org/about

芥子气于 WWⅠ 后期（ 1917 年 7 月）首先由德军大量使用，其后各国军队相继效仿，造成大量人员伤亡。其伤亡率占毒剂总伤亡人数 130 万的 88.7 ％，故有“毒剂之王”之称。从 WWⅠ 到“两伊”战争使用证明，芥子气是经过“战争考验”的最有效的化学战剂之一。

一种高效除草剂，容器标志条纹为橙色，故名“橙剂” (Agent Orange) 。 越战后，越战中曾在南方服役人的孩子出生缺陷率高达 30% 。南方服役过军人妻子的自发性流产率也非常高。美国的越战老兵： 9 种疾病被证实与“橙剂”有直接关系，包括心脏病、前列腺癌、氯痤疮及各种神经系统疾病等。

In response to concerns about the health effects of deployments following the 1991 Gulf War, DoD conduct prospective epidemiological research to evaluate the impact of military exposures. more than 200,000 participants meets this critical need.

Mega cohort studyFrom a handful of exposure variables to the number of genes, the number of hypotheses that could be tested simultaneously has increased exponentially.

To solve this problem, consortia pool data from existing cohorts of tens of thousands of participants. A new generation of mega cohorts with massive biobanks is being established in North America and Europe.

Gaziano J M. The evolution of population science: advent of the mega cohort[J]. JAMA, 2010, 304(20): 2288-2289.

Mega cohort study

Robert N. Hoover, MD, ScD, Director Epidemiology and Biostatistics Program Division of Cancer Epidemiology and Genetics, National Cancer Institute

Robert N. Hoover, MD, ScD, Director Epidemiology and Biostatistics Program Division of Cancer Epidemiology and Genetics, National Cancer Institute

Implications of life course processes in epidemiology and public health

• The understanding of mechanisms involved over the life course – Allows a better understanding of how the psychosocial

becomes biological – Give some targets for intervention aiming at reducing social

inequalities in health

• Many interests of life course approach but also important practical issues– Regarding data and study requirements with this approach– The need to think and model the mechanisms by which

various factors influence health in a more relevant way

Cohorts used for life course studies

• Prospective design

• Multiple measures– Socioeconomic factors: housing, social class, education, income,

occupational exposures– Psychosocial factors– Health behaviours– Health measures: subjective measures and objective measures

(clinical examination)– Access to care

• Biological samples

• Repeated collection of data over time

• Long follow-up, from the birth to adulthood

Birth cohort studies+++

Birth Cohort Studies: some examples (1)

• In Great Britain:– 1946 National Survey of Health and Development (NHSD): N=5 362– 1958 National Child Development Study (NCDS): N=17 773– 1970 British Cohort Study (BCS): N=16 135– 1991-1992 The Avon Longitudinal Study of Parents and Children (ALSPAC):

N=14 541– 2000-2001 Millennium Study: N=18 819

• In United States– The Child health and development Study (1959-1966): N=around 20000– The Early Childhood Longitudinal Study (ECLS-B), 2001: N=14 000

• In New Zealand– The Dunedin Cohort (1972-73): N=1 037

• In Australia– The longitudinal Mater University Study of Pregnancy (MUSP), 1981-1984:

N=around 8 000

Birth Cohort Studies: some examples (2)

• In Scandinavia– The Norwegian Mother and Child Cohort Study (MoBa),

1999: N=100 000 – The Danish Cohort Study (1996): N=around 60 000– The Stockholm Birth Cohort (1953): N=14 292

• Also in “emerging countries”– In Brazil: The 1982 Pelotas birth cohort study: N=5 914

• In France – EDEN cohort (2003): N=1 900 – ELFE (2011): N=18 000

Some issues with birth cohort studies

• Different follow-up– Relevancy for some chronic diseases?

• Various number of participants– Power?

• Data collection at different times in life course– Impact for studying sensitive period?

• Included variables changed according objectives• Biological samples are not always available, standardized (urine,

blood, serum) and collected repeatedly• Ask questions about generalizations

– Over time : relevancy to use results from 1958 NCDS cohort showing link between adversity and cancer for now? Definition of adversity still relevant?

– Across countries: relevancy to use results observed in UK to characterize the French situation

• Expensive and long time before results– Request to think to alternative method

Alternatives to birth cohort studies

• Using existing cohorts or databases– Less expensive– Less time to have results– Solution to increase power of study– Solution to manage follow-up– Solution to have create database including biological sample

• The main point is then to “rebuild” life course – Data from archives

• Dependant on the quality and the availability of variables collected in archives

– Retrospectives Studies• Recall bias• key question: which variables are relevant to characterize life course in a

retrospective approach?– Databases linkage (Scandinavia+++, Constances cohort)

• Interesting if various databases available: biological, clinical, social, administrative

• Need a easy, feasible linkage• Questions of confidentiality

1. Valuable in rare exposures.

2. Can study multiple effects of a single exposure.

3. Exposure happened before outcome (Temporality)

4. Can calculate incidence rates.

5.5. Can quantify Risk, Relative risk, & Attributable RiskCan quantify Risk, Relative risk, & Attributable Risk

6.6. Dose response ratio can be calculated.Dose response ratio can be calculated.

7.7. Low potential for bias than case-control studyLow potential for bias than case-control study

Advantages of cohort studies

But important issues with cohorts• Methodological issues

– Mediation• Difficulty to measure direct and indirect effect

– Need to know variables of confusion at least the important ones– Need to collect them, repeatedly

• Difficulty to analyse mediation– What methods? In longitudinal situation?

– How to disentangle mechanisms involved over time

• Practical issues– Follow-up

• Attrition bias: how to manage missing values, particularly when missing at random assumption wrong

– Boot strap methodology– Hidden Markov model

– Quality of the measures: declarative vs objective • Recall bias, measurement errors

– Non random exposures (indication bias)

• Risk of bias by using cohorts that can lead to false conclusions

Diagram of Hypothetical 6-Year Cohort Study to Identify Risk Factors for Facial Acne in Teenagers

1000 12-year-olds without acne

500 18-year-olds without acne

900 15-year-olds without acne

50 with Acne

300 with Acne

5 moved

10 no answer

35 refused

10 moved

40 no answer

48 refused

2 deaths 350 incident cases of acne over 6 years

6-yr Follow-up Rate = 850/1000 = 85%

Incidence Rate of Acne = 350/5475 PY = 63.9 per 1000 PY

Conclusion• Cohorts play an increasing role in epidemiology and represent an

investment for society

• Lead to important findings by giving opportunities to – Test the effect of multiples exposures in various diseases– To consider the life course in analyses and thus increase our understanding

on mechanisms and chains of causality

• But cohorts present important limitations that can have a huge impact on conclusions in particular– Attrition bias, missing data and measurements errors

• Need – People and money – Standardised processes in particular to follow people – Strong development regarding biostatistical methodology to control

limitations of cohorts

Question?

Assigned readings, session 2:• Grimes DA, Schultz KF. Cohort studies:

marching toward outcomes. Lancet 2002;359:341-5.

• What is Mega cohort study? Please list its advantages and disadvantages.