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NATIONAL RESEARCH COUNCIL

COMMISSION ON LIFE SCIENCES

2101 Constitution Avenue Washington, D.C. 20418

BOARD ON RADIATION EFFECTS RESEARCH

NAS Room 342 TEL: (202) 334-2232 FAX: (202) 334-1639

Dr. James M. Smith

Chief, Radiation Studies Branch

Centers for Disease Control and Prevention

4770 Buford Highway, NE Mailstop F35 Atlanta, Georgia 30341-3742

July 27, 1998

Dear Dr. Smith:

As you are aware, on December 18, 1997, the Committee on an Assessment of CDC Radiation Studies met in Washington to review the analysis plan for the Hanford Thyroid Disease Study (HTDS). The committee had been asked to comment on two specific topics in connection with the recent addendum to that plan: how the HTDS analysis will deal with information about exposures of study participants to iodine-131 released from the Nevada Test Site (NTS) in the course of weapons testing and how the HTDS analysis will deal with uncertainties in the estimated doses from the Hanford site.

Before its meeting, the committee was provided with the following materials:

  • Hanford Thyroid Disease Study Analysis Plan, June 30, 1997. This analysis plan describes the approach that was proposed to be taken in 1997 to meet the objective of the Hanford Thyroid Disease Study (HTDS) which is to determine whether thyroid disease has increased among persons exposed to radioactive iodine released from the Hanford Nuclear Site between 1944 and 1957. The plan is organized into 3 parts which describe the specific objectives of the study, the definitions of the variables which will be analyzed, and the analytic methods which will be used.

  • Addendum to Analysis Plan, November 24, 1997. This addendum to the June 30, 1997 analysis plan described above addresses the two topics reviewed by the Research Council committee: (1) How the HTDS analysis will deal with information about exposures of study participants to iodine-131 released from the Nevada Test Site (NTS); and (2) How the HTDS analysis will deal with uncertainties in the estimated doses from the Hanford site.

  • Peer-review comments on the January 27, 1997 draft of the HTDS analysis plan. The CDC submitted the HTDS analysis plan to scientists for review and evaluation. The comments from 4 reviewers were distributed to the Research Council committee members.

  • Summary of revisions to the January 27, 1997 draft of the HTDS analysis plan. This document summarizes the various revisions including the addition of paragraph numbering and thyroid volume as an outcome to be analyzed, the moving of paragraphs



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NATIONAL RESEARCH COUNCIL COMMISSION ON LIFE SCIENCES 2101 Constitution Avenue Washington, D.C. 20418 BOARD ON RADIATION EFFECTS RESEARCH NAS Room 342 TEL: (202) 334-2232 FAX: (202) 334-1639 Dr. James M. Smith Chief, Radiation Studies Branch Centers for Disease Control and Prevention 4770 Buford Highway, NE Mailstop F35 Atlanta, Georgia 30341-3742 July 27, 1998 Dear Dr. Smith: As you are aware, on December 18, 1997, the Committee on an Assessment of CDC Radiation Studies met in Washington to review the analysis plan for the Hanford Thyroid Disease Study (HTDS). The committee had been asked to comment on two specific topics in connection with the recent addendum to that plan: how the HTDS analysis will deal with information about exposures of study participants to iodine-131 released from the Nevada Test Site (NTS) in the course of weapons testing and how the HTDS analysis will deal with uncertainties in the estimated doses from the Hanford site. Before its meeting, the committee was provided with the following materials: Hanford Thyroid Disease Study Analysis Plan, June 30, 1997. This analysis plan describes the approach that was proposed to be taken in 1997 to meet the objective of the Hanford Thyroid Disease Study (HTDS) which is to determine whether thyroid disease has increased among persons exposed to radioactive iodine released from the Hanford Nuclear Site between 1944 and 1957. The plan is organized into 3 parts which describe the specific objectives of the study, the definitions of the variables which will be analyzed, and the analytic methods which will be used. Addendum to Analysis Plan, November 24, 1997. This addendum to the June 30, 1997 analysis plan described above addresses the two topics reviewed by the Research Council committee: (1) How the HTDS analysis will deal with information about exposures of study participants to iodine-131 released from the Nevada Test Site (NTS); and (2) How the HTDS analysis will deal with uncertainties in the estimated doses from the Hanford site. Peer-review comments on the January 27, 1997 draft of the HTDS analysis plan. The CDC submitted the HTDS analysis plan to scientists for review and evaluation. The comments from 4 reviewers were distributed to the Research Council committee members. Summary of revisions to the January 27, 1997 draft of the HTDS analysis plan. This document summarizes the various revisions including the addition of paragraph numbering and thyroid volume as an outcome to be analyzed, the moving of paragraphs The National Research Council is the principal operating agency of the National Academy of Sciences and the National Academy of Engineering to serve government and other organizations

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describing the handling of out-of-area participants in exposure-outcome analyses, and the modifications made to the list and definitions of the primary and alternative thyroid disease outcomes in appendix 2 of the HTDS analysis plan. In addition, specific responses to comments from 5 members of the HTDS Advisory Committee and the 4 external reviewers are summarized. Executive summary of the Hanford Thyroid Disease Study study protocol, May 26, 1993. Executive summary of the pilot-study final report, January 24, 1995. When the committee met, Drs. Scott Davis and Kenneth Kopecky, members of the staff of the Fred Hutchinson Cancer Research Center and the principal investigators in the HTDS, enlarged on the description of the proposed analysis and the changes in the original plan prompted by the need to address the additional source of exposures and the uncertainties in dose. The original plan has been reviewed by the Radiation Studies Branch of the Centers for Disease Control and Prevention, by several ad hoc peer reviewers, and by the Hanford Thyroid Disease Study Advisory Committee. The comments of those varied reviewers were shared with the committee, and the HTDS investigators' responses to them were presented in writing. Overall, the committee was impressed by the clarity and thoroughness of the analytic plan and compliments the investigators on the care with which they have responded to the need to develop such a plan. Moreover, the study has been thoughtfully and competently executed, and the degree of attention to detail will no doubt provide data of high quality. The investigators have successfully traced 94% of the historical study cohort established 50 years ago–a very impressive achievement. However, the investigators are now faced with the daunting task of analyzing this large and complex data set, which offers almost unlimited possibilities for model-building and hypothesis-testing. The very richness of the data can produce problems, specifically problems that arise from multiple comparisons, some of which will inevitably be statistically significant. To better distinguish between an effect of interest and a chance finding, we recommend that the investigators delineate with more rigor the choices to be made about variable specification and by setting forth a priori a subset of primary analyses (perhaps 10) believed to test the research question(s) directly. A focused selection and description of the primary hypotheses to be tested will provide guidance both to investigators and to reviewers at the conclusion of the data analysis and will avoid to some extent the statistical problems arising from multiple comparisons. The basic analytic plan for the study envisages a stratified linear exposure-response model to accommodate dichotomous and continuous variables and to account for uncertainty in dose estimates. The presentation of the plan to the committee included a discussion of the proposed revisions regarding the handling of uncertainty for both the HTDS and NTS doses. For the HTDS doses, a dose-estimation program, CIDER, was developed to perform a Monte Carlo simulation of individual doses, taking into account the uncertainties in various components of the exposure model. Dose estimates and

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uncertainties are estimated from 100 realizations generated with this model for each individual. Methods for estimating important functions, such as the score vector and observed information matrix, were described. Sampling of vectors of observed doses has been done using CIDER. For specification of the distribution of true HTDS doses, the investigators have assumed a lognormal distribution, with mean and variance dependent on year of birth and gender. The committee 's review of this plan raised several questions and prompted several recommendations to assist the investigators. Among the questions were the following: Will people with nonconfirmed disease be included in the primary analysis? Can doses be estimated with reasonable accuracy and precision for individuals moving into and out of the study area? Will self-reported food-consumption data be compared with default food-consumption data? Can non-participants be characterized better? Clinically inapparent thyroid disease is common, so the cumulative prevalence of this disease will be affected by “workup bias.” The committee is concerned that workup bias might correlate with the widely disseminated maps of representative doses. Can this possibility be addressed? As noted earlier, two specific challenges to the investigators are the development of an analytic plan to take into account the additional thyroid dose to Hanford study subjects emanating from NTS fallout and the uncertainty in the dose estimates. In the course of the committee 's review of these two issues, the committee recommended that the HTDS consider an alternative analysis that allows somewhat better control for age at irradiation. Thyroid Dose from NTS Fallout: The HTDS investigators have proposed to deal with NTS fallout by treating it as a confounding variable in their analyses, rather than by attempting to estimate possible risk associated with NTS fallout, because estimation of NTS-associated risk was not part of their mandate and problems of comparability and uncertainty in doses arise in the combination of two sets of doses. They propose to create strata of NTS doses by calculating, for each person, “average” doses per NTS test based on the representative NTS doses according to age and county of residence, but not factoring in milk-drinking habits, and so on, while summing across all NTS tests. The public that has been concerned with radiation dose to the thyroid gland has consisted of persons living in the vicinity of Richland, Washington, and persons living “downwind” relatively close to the NTS. The recently released National Cancer Institute study of the fallout of I-131 from weapons tests at the NTS will expand the concern to many more Americans who are now about 40 years old and older. Therefore, whatever is

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done with respect to the Hanford Environmental Dose Reconstruction (HEDR) data and HTDS is ultimately going to affect more than the Hanford cohort. Any decisions made with respect to the HTDS need to keep this in perspective. That said, the committee recognizes that the NTS data must be incorporated into the HTDS in some manner. The HTDS investigators basically have three options with regard to the NTS doses: they can ignore them, they can treat them as a confounding variable, or they can seek to incorporate them directly into their analysis. With respect to those options, the committee notes the following: Do nothing with the NTS data. This could seriously undermine public acceptance of an otherwise carefully executed study. The public knows that the NTS data exist; ignoring the data will be seen as scientific dissembling. In the committee's view, this is not a viable option. Incorporate the NTS data into the HTDS as a confounding variable, as advocated by the HTDS investigators. This would make the analysis more timely and more scientifically defensible. Inclusion of NTS fallout in radiation dose determinations as a confounding variable also recognizes the effect better, although it might not be perceived that way by the public. The approach might be more acceptable to the public if an estimated NTS dose is given. People who want to calculate their dose or the dose to their relatives would be able to add or ignore this additional estimated dose. Incorporate the NTS directly into the model. Ideally, one would determine directly the total risk and the contribution of each set of exposures to the total risk. Thus, a formal treatment of the NTS contribution to total risk directly addresses the concerns of the public, although it adds some complexity to the study. In principle, the HTDS could apply the National Cancer Institute (NCI) dose data in their current form for the relevant exposure period of individuals or groups, report the total thyroid risk for these individuals or groups, and provide the fractional contribution of the NTS fallout to the total risk. It need not recalculate the NCI data but could apply the appropriate age-specific risk factor for the county-averaged exposure that occurred in 1951-1961. The basic issues are using as much information as possible on the total dose received, but not lumping together data of varying quality and individual specificity. Option 2 seems to afford the best approach to address both issues simultaneously. The committee recommends that the investigators discuss both options 2 and 3 in their analytic plan and develop a convincing case for reliance on the second rather than the third option in the analysis. In dealing with the NTS data in the study, the committee notes that the dispersion in the distribution of NTS doses might be small in this population and that the uncertainties are probably large, so there could be considerable misclassification of this potentially confounding variable, which means that there could be residual confounding.

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However, if there is little correlation across study subjects between the HTDS doses and the NTS doses, as seems likely, then there might well be little confounding in any case. The committee concurs that treating NTS doses as a confounder is reasonable and that the NTS dose information, if developed, should be preserved, inasmuch as it might be of interest in the future to evaluate the impact of the NTS doses on thyroid risk in the context of the NCI NTS-fallout effort and this study group might prove to be one of the few available in which it could be evaluated. No matter how the NTS doses are incorporated into the HTDS analysis, the dose-conversion factors from HEDR need to be compared with the dose-conversion factors for the NCI NTS study. Better Control for Age at Irradiation: The committee recommends that the HTDS investigators consider an alternative analysis that allows somewhat better control for age at irradiation than their proposed method of merely using age at first exposure. Some subjects will have been exposed at (or before) birth but will not experience a major increment of exposure until several years later at a time corresponding to when “pulses” of exposure occurred. From the Japanese atomic-bomb data and a few medical-irradiation studies, it is known that there is a very steep gradient of risk per unit dose according to age at exposure (relative to risks posed by irradiation at ages 0-4, for example, the data show risks only 50% as high for irradiation at ages 5-9 and only 20% as high for ages 10-14). An alternative mode of analysis therefore might be to use the accumulated exposures received in each age category (0-1, 2-4, 5-9 and 10-14 years) as variables in the model. Comparison of these models would shed light on whether the simpler model, with a single exposure variable and initial exposure age as a covariate, adequately accounts for the variation in risk by exposure age. Likewise, the possible confounding effects of NTS fallout exposure could be sorted out more accurately if ages at receiving this exposure were factored into the analysis. The notion that age at exposure is important in determining risk also has implications for the proposed method of treating uncertainties in estimating risk. The investigators propose to combine groups with similar estimated doses (HTDS Analysis Plan, Addendum, p.7). One might not want to do that if exposures were occurring at different ages, became the risk implications of equivalent doses probably vary according to age at exposure. Dose Uncertainty: Throughout the analysis and interpretation of the HTDS data, the limitations of the dose term must be acknowledged. The HTDS investigators are cognizant of this and have incorporated many safeguards against systematic error into the study, but the resulting dose estimates are highly uncertain, and the use of self-reported information in the construction of the dose estimates presents an opportunity for bias, such as over- or under-reporting of activities that might substantially affect exposure estimates. The investigators are urged to evaluate further the use of some of the interview data to corroborate the HEDR exposure estimates and the default options.

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Modeling has inherent limitations that need to be acknowledged candidly. Given the insufficient data available on Hanford, there will always be considerable imprecision in the individual doses, and it is unlikely that further refinements in the model will increase the precision of these doses substantially. It warrants noting, too, that although the uncertainty in some of the components of the model has been accounted for, this is not true of all of them, and the total uncertainty is likely to be greater than has been publicly stated. I trust that you will not hesitate to call me or Dr. Evan Douple if you have any questions. Sincerely, William J. Schull Chairman Committee on an Assessment of CDC Radiation Studies wjs:s cc: Dr. Evan Douple (BRER, Study Director) Members of the Committee