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The most authoritative basis for supporting a medical intervention is a meta-analysis of all sufficiently rigorous relevant randomized controlled trials. In this issue Saquib, Saquib and Ioannidis present an unprecedentedly thorough survey of 9 meta-analyses and 48 trials representing the best available evidence for the effectiveness of a range of screening interventions. Some of the evidence reviewed has been argued over before. In the case of breast cancer, probably the most debated screening intervention, a series of large trials in the 1970s and 1980s provided what seemed to be clear evidence that screening saved lives, and countries across the developed world introduced programmes. Yet, in 2000, a meta-analysis concluded that there was no reliable evidence for breast screening. The authors, Olsen and Gotzsche, had identified eight trials but argued that the results of the six more or less favourable trials could not be trusted and that only the two more equivocal trials were sound. The inclusion of one of the larger trials, the Swedish twocounties trial, should have been enough to reverse Olsen and Gotzsche’s conclusion. They had argued that this trial had to be excluded in part because the average ages of the two groups were slightly different. The point is not that this difference—which was only 5 months—affected the results, but rather that any difference between two such large samples casts suspicion on the claim that they were randomly allocated. A further concern was that the investigators reviewing deaths among participants knew which arm of the trial a woman was in when they decided whether to count her death as caused by breast cancer death or not. Whether or not these concerns are sufficient to warrant the exclusion of the trial is a matter of judgement and judgements, in this case, differed. Olsen and Gotzsche were not the first or the last to attempt a meta-analysis of breast screening: there have been more reviews than there are trials to review. The arguments have been bitter, but have led towards consensus. Gotzsche updated his analysis in 2011, including more trials and finding overall support for the conclusion that screening reduces breast cancer deaths. An independent panel of UK experts, commissioned to look at the evidence, published a report in 2012 that drew on Gotzsche’s revised review to conclude that screening does reduce breast cancer deaths. The United States Preventative Services Task Force has made a similar assessment. Saquib, Saquib and Ioannidis, following Gotzsche’s updated analysis, give breast cancer as a case where screening reduces disease-specific mortality. But there’s the rub. If breast cancer deaths are reduced, but all-cause mortality is unaffected, is this because detecting the latter requires that more statistical power be deployed? Or is it, as Gotzsche has suggested, because the harms of screening increase deaths from other causes? The most serious cause of harm is overdiagnosis. The independent UK panel took the view that the best estimate of overdiagnosis could be provided by comparing the rates of cancer detection in the screened and the unscreened groups of randomized controlled trials. The problem is that when most trials ended, screening was offered to the women in the control groups, creating overdiagnosis in the follow-up period. The panel therefore restricted their attention to three trials in which no screening was offered to the control group during follow-up. This is a very limited set of data. Saquib, Saquib and Ioannidis ignore the question of harms presumably because there simply are not enough RCT data to review.

Commentary: Tempering expectations of screening: what is the most authoritative advice we can give, given the data that we have?