On the Concept "Study Day Zero"

ON THE CONCEPT "STUDY DAY ZERO" ALBERT WEISSMAN* I. Diem Perdidi No one likes to lose track of time, be it an hour, a day, or a year. It doesn't matter whether the loss stems from waste or miscalculation. It is disturbing in any case, because most of us come to regard time as an unlimited linear continuum of events without unexpected gaps. We intuit that under almost all conditions time can extend indefinitely both backward and forward. That is the reason so many laymen have conceptual difficulties with the big bang theory of cosmology. We treasure keeping orderly track of time. That is why we maintain clocks and calendars . Technological advances or quirks of history occasionally disrupt the perceived dependable now of our calendars. For instance, when Magellan 's crew went ashore in 1522 in the Canary Islands after the famous round-the-world expedition, they were advised by the islanders that they had lost a day: "It was Thursday, which was a great cause of wondering to us, since with us it was only Wednesday. We could not persuade ourselves that we were mistaken" [I]. When Pope Gregory XIII's commission reformed the calendar in 1582, decreeing that during that year Friday, October 15, would immediately follow Thursday, October 4, 10 days were forever lost, resulting in outcries throughout the world. For political reasons, the changes were not adopted in Protestant Germany until 1698, in Great Britain and its colonies until 1752, and in Russia until 1918, by which time even more days had to be eliminated [2]. And once in a while, we are reminded that during the last few milennia there has already been a l-year discontinuity in our civilization's way of reckoning time, occurring between the years 1 b.c. and a.d. 1. The year that immediately followed 1 b.c. is not considered to have been *Department of Clinical Research, Phzer Central Research, Croton, Connecticut 06340.© 1991 by The University of Chicago. All rights reserved. 003 1 -5982/9 1 /3404-0736$0 1 .00 Perspectives in Biology and Medicine, 34, 4 ¦ Summer 1991 579 year zero. Therefore, when we subtract a negative (i.e., b.c.) year from a positive (i.e., a.d.) year to determine how many years have elapsed between the two, we must subtract an additional year—against all ordinary rules of arithmetic—to make up for the missing year zero. As an illustration of the problem, killjoys [3, 4] were compelled to remind the literati, intent on celebrating the bimillennium of the birth of Virgil during 1930, that Virgil (born 70 b.c.) would have been only 1999 years old in October 1930 and that his actual two-thousandth birthday was not scheduled to take place until 1931. Wrote one of these 1930 authors, presciently, "when Dionysius Exiguus devised an improved system of chronology, he could have saved future historians and computers some annoyance if he had designated the year following b.c. one as the year zero. He was possibly not acquainted with zero and its helpful properties " [4]. Had there been a year designated as year zero, there might now be unanimity that the third millennium of the Christian era will begin with the year 2000. II. Clinical Studies: Should There Be a Study Day Zero? A discrepancy analogous to the calendar year zero gap besets many clinical pharmacology studies, yet few investigators seem to notice. The same problem arises in other biological areas, such as animal toxicology and perinatal research. Like rocket launches, drug trials undergo a countdown period during which the investigator gathers and checks resources, makes baseline measurements, and prepares for the exciting events expected after the first experimental treatment, which is often taken to mark the formal beginning of the study. The most common time units in a clinical study countdown are days, not seconds, as in a rocket launch, or years, as in b.c. dating, but they could be milliseconds, hours, weeks, or any other unit. Often the days just before launch are explicitly assigned negative numbers. For example, baseline measurements may be scheduled for days —3, —2, and — 1. What should we number the study...