figure that shows clearly the steps involved in the dose-estimation process to be used in Phase III. The current Figure 5 is extremely confusing: What does "environmental transport" (Box 8) contain, given that it has inputs of "source term", "animals", "cows/goats", and “commercial milk producers pooled”? How does "radiation released and transported" (Box 2) get to "animals ate contaminated vegetation" (Box 4) without going through "environmental transport" (Box 8)? No reference is provided for either the proposed model or any predecessors.
The effort required, or the time required, appears to have been substantially underestimated. Field work is said to require 2 years (page 20). Having two teams examine 5000 subjects means 1250 examinations per team per year, or about six examinations per team per working day. That is impossible, given that examinations are expected to take 60-90 minutes each.
The study protocol does not appear to have been adequately assessed with respect to potential sources of bias. In view of the likely marginal statistical power of the study, a thorough discussion, and preferably a quantitative evaluation, of potential sources of bias is essential, even for small potential biases. Examples follow:
Page 20: To minimize the possibility of bias in the review of ultrasound images, it is important that survey locations not be identifiable to reviewers on the basis of characteristics of the images. Will random study identification designation be used, and how will care be taken to avoid minor instrumentation or operator variation that could identify survey subjects in high- vs low-dose regions?
Page 22: The contact diagram shown on page 22 has the examiners interpreting the questionnaire. If a nodule is found, the subject is told and schedules fine-needle biopsy before completing the questionnaire. Subjects with immediately detected nodules thus have a potentially traumatic event thrust on them before they complete the questionnaire. That could bias their answers. Moreover, the examiners themselves will know the nodule status of the subject before they perform the review of the questionnaire with the subject—another potential source of bias.
Page 43: It seems that the "control" group will be substantially different from the "dosed" groups because of the inclusion of all the late movers. What will be done to evaluate whether that introduces a bias?
Page 48, Table 13: The table gives insufficient information to make any judgment about recall bias. In particular, there is no indication of the standard deviations. The table contains information on only 1528 subjects. Why so few, and was the method of selection determined to minimize the introducing of bias?
Page 49: The examiners are supposed to be unaware of exposure status, but they are going to start administering the questionnaire before they do the physical examination, and they are presumably going to talk to the subject and so might be made aware of the exposure status from the information so gained. There are instructions to the examiners to avoid such small talk, but it appears that it would be difficult or impossible to control or prevent it.