GJRRENT TIERAPEIJTK R~~SEARUI”~ VOL. 61, No. 4, APRIL 2000

Editorial Comment

Why Studies Are So Much Larger

We have passed from the era of “medium-sized” studies, like the Scandinavian Simvastatin Survival Study (4444 people) and the West of Scotland Coronary Pre- vention Study (6595 men) to “large” studies, like the studies of fever in children (~50,000 participants). Now we are faced with the Japan Lipid Intervention Trial (J-LIT), which had 52,421 women and men in 2 cohorts. Why have studies grown so large?

One reason is that investigators are trying to make the conclusions broadly applicable. To do so they have to enroll a representative sample of the general population. Matsuzawa and colleagues manage to achieve this goal by enrolling a cross-section of people from all sectors-rural, urban, and suburban areas; cold and warm climates; plains and mountainous terrain. Certainly, the J-LIT population mirrors the general Japanese population with moderately elevated cholesterol lev- els. The trial’s conclusions will likely reveal some truths about low-dose treatment with simvastatin, such as whether it lowers low-density lipoprotein cholesterol levels.

As investigators ask more complex questions or, as in the J-LIT, several ques- tions at once, study sample sizes must be increased commensurately. Matsuzawa and associates are trying to establish primary and secondary prevention, the effect of risk factors, and, in fact, changing the natural history of hypercholesterolemia. Although they state that the large cohort size will enable them to analyze risk factors relating to another disease (cancer) and even to accidents, I doubt that they have enough people enrolled to reach solid conclusions. However, we would be interested in the relationship between lower cholesterol levels and accidents and, I might add, suicide, violence, and other forms of aberrant behavior. All in all, it is am ambitious program.

When end points (1) occur rarely, (2) can be caused by events not under study, and (3) are difficult to diagnose clearly, a large study population is needed to deal with the built-in error and achieve statistical significance for a meaningful differ- ence. Of course, if the whole project is to be completed in a relatively short time, the sample size must be large enough to allow expeditious collection of data. Other issues such as noncompliance, loss of patients to follow-up, and continuing active investigator involvement also must be considered.

When conducting such gargantuan studies, considerable time and effort must go into the planning phases to ensure that every aspect has been considered, potential problems have been addressed, contingencies reviewed, and solutions put in place. If any fault is left uncorrected, years of hard work may go down the drain. In many ways, the worst possible outcome would be that the volunteers gave their most precious resource, themselves, as well as their hard work, to a fruitless proj- ect. This article by the J-LIT investigators allows us to make judgments about the study and its hope for a successful outcome.

Michael Weintraub, MD Editor-imChief

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