A New 500,000-person National Cohort or Pooling Existing Cohorts?

Recently, raging debates and power struggles have been looming in the world of epidemiology and genome research between two factions-- one supporting the establishment of a massive national cohort, the other supporting the approach of pooling existing large cohorts. Several leading scientists debated these opposing approaches in a recent pair of articles in Nature.

Francis Collins, director of the National Human Genome Institute of the NIH, envisions forming a massive cohort project of 500,000 participants to create a vast database of genetic and biomarker data linked to information about participants' geography, diet, lifestyle and many other factors. Collins cites the advantages of representativeness of the national cohort population, standardized methods of assessment, new technologies of assessment, updated exposure data, more current age cohort, wider age ranges, and more minorities participants.

In contrast, Walter Willett, chairman of the Department of Nutrition at the Harvard School of Public Health, backs a more efficient approach that pools existing cohort studies. Given the very tight government budget for medical research in recent years, he fears many other important high priority projects will get squeezed. Additionally, existing cohorts comprised of 1,400,000 participants with 845,000 biological samples can give answers quickly without waiting 10, 20, or 30 years or more.

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"If it only cost a few hundred million dollars to start a new cohort, there wouldn't be much of an issue at all," Willett said. But with a projected cost of $3 billion or more for a study that includes subjects representative of the country's ethnicities and walks of life, "then it's going to displace a lot of other research at a time when research is being hugely squeezed," he said.

On the other hand, a new cohort study holds several advantages over a cohort that combines existing studies, said Collins. For instance, researchers could apply exactly the same methods to gather data from each subject, include enough minorities and other groups without statistical adjustments, collect data on entire lifespans, and employ the latest technology, such as mass spectrometers.

One advantage of larger cohorts that was not explored in the commentaries is that their standardized approach makes it easier to combine data on subjects, while some detail gathered by small cohorts could be lost when they are pooled, said Willett. When researchers examine pooled data, they must use a "common denominator" of data, potentially ignoring variables that had been gathered by some studies, he said.

But this drawback is partly countered by another advantage of pooled studies: time. In addition to its high cost, a new, large-scale cohort study will take as long as 10 years to produce any results, due to time-consuming planning and enrollment, as well as the time needed to research common diseases, argues Willett.

In contrast, combining existing cohorts would take much less time, given that most of the data already exist, Willett says. He lists 13 studies -- such as the Nurse's Health Study -- that he feels are suited for pooling, including about 1.4 million subjects and 845,000 biological samples. However, some are hesitant, as such a project would place nearly a large proportion of the resources in the hands of Harvard.

Willett estimates the kind of cohort study model he envisions might require a budget of $20 million to $50 million per year, with perhaps 50-75 percent coming from existing funding from smaller constituent cohort studies.

A pooled cohort project is "certainly a much more cost-efficient strategy," said Roberta Ness, chair of the University of Pittsburgh department of epidemiology. However Ness adds that "It won't get you everything -- there will be real limitations with respect to the age composition of the cohorts, the baseline data collection, [and standardization of] the specimen-collection techniques," she said.

A pooled cohort's shortcomings will hinder the study of diseases that develop early in life, such as asthma and major psychoses, because it would lack adequate data from children, argues Collins. He is also concerned that research into changing environmental factors, such as emerging infections, will suffer, because researchers using a pooled cohort might not concentrate on updating their information past a number of basic variables.

This isn't an insurmountable problem, insisted Carolyn Williams, chief of epidemiology in the division of AIDS at the National Institute of Allergy and Infectious Diseases, that gaps like this are routinely filled in with existing pooled cohorts, where researchers check study subjects for a new set of variables once the cohorts have been pooled.

The NHGRI has already taken expensive steps toward a large cohort study, including its $40 million Genes and Environment Initiative, which is developing genotyping facilities, data analysis infrastructure, disease biomarkers, and better tools for measuring environmental exposures.

W. Willett, "Merging and Emerging Cohorts," Nature, January 18, 2007.
F. Collins, "Necessary but Not Sufficient," Nature, January 18, 2007.
C. Womack. Cohort models debated. [THE SCIENTIST 17th January 2007]