Details of the study design have been published previously (Stezhko et al. 2004
; Tronko et al. 2006a
). In brief, the cohort includes individuals with direct thyroid radioactivity measurements made in May or June 1986 who were < 18 years of age on 26 April 1986 and resided in selected areas in the neighboring Chernihiv, Zhytomyr, or Kyiv oblasts of Ukraine in 1998. An oblast is an administrative subdivision similar in size to a state or province. Of 32,385 individuals originally selected for the study, 10,307 (31.8%) could not be traced primarily because of the long interval between the accident and the start of screening, as well as high mobility of this young cohort; 2,466 (7.6%) were traced but were not eligible or available to participate; and 6,369 (19.7%) were traced but refused to participate or failed to attend the screening, resulting in 13,243 (40.9%) individuals who were screened for the first time between 1998 and 2000. After additional exclusions described elsewhere (Tronko et al. 2006a
), analysis of thyroid cancer prevalence was based on 13,127 individuals. In the present analysis, we also excluded 45 individuals who were diagnosed with thyroid cancer as the result of the first screening examination, 3 individuals who were found to have thyroid aplasia, and 566 individuals (4.3%) who were considered lost to follow-up because they participated in only the first screening examination. We included 1 individual who was diagnosed with incident thyroid cancer 8 years after the first examination but was previously excluded from the analyses because of incomplete data at baseline. This resulted in a total of 12,514 individuals included in the present analysis.
The study was reviewed and approved by the institutional review boards of the participating organizations in Ukraine and the United States, and all participants (or their legal guardians for those < 16 years of age at the time of screening) signed an informed consent form.
Screening examination. After a first screening examination in 1998–2000, three biennial thyroid examinations were conducted between 2001 and May 2007 either by a mobile screening team or at the Institute of Endocrinology and Metabolism (IEM) in Kyiv. Screening procedures were standardized and included thyroid palpation and ultrasonographic examination by a trained ultrasonographer; independent clinical examination and palpation by an endocrinologist; a serum sample; a spot urine sample; and a series of structured questionnaires eliciting information on demographics, medical history, and items relevant to thyroid dose estimation, such as residential history, milk consumption, and iodine prophylaxis in May–June 1986.
Before 2004, the thyroid gland was examined using 7.5 MHz probes, either an electronic linear transducer (Hitachi Medical Systems, Tokyo, Japan; or GE Logiq 100, General Electric Company, Milwaukee, WI, USA) or a mechanical sector probe with water bag kit (Tosbee SSA 240s with 7.5 MHz SM-708A probes; Toshiba Corp., Tokyo, Japan). Beginning in 2004, this equipment was replaced with a laptop-based mobile system that used a 10-MHz linear probe (Terason Ultrasound, Burlington, MA, USA). Details of nodules, echostructure, and echogenicity were recorded. The thyroid volume was calculated based on the volume of an ellipsoid as described by Brunn et al. (1981)
Serum assays. Antibodies to thyroid peroxidase (ATPO), thyroid-stimulating hormone (TSH), and thyroglobulin (TG) were measured in all available serum samples (99% of the cohort) with LUMitest immunochemiluminescence assays (BRAHMS Diagnostica GMBH, Heningsdorf, Germany) using an AutoLumat LB 953 Luminometer (Berthold, Pforzheim, Germany). Based on evaluation of reference limits in a reference sample from our cohort, an elevation of ATPO > 60 U/mL, consistent with BRAHMS, was considered positive. Similarly, based on evaluation of reference limits in a sample from our cohort, reference limits of TSH were set between 0.3 mIU/L and 4.0 mIU/L. According to the manufacturer, reference limits of TG measurements were between 2 ng/mL and 70 ng/mL.
Thyroid cancer cases.
Incident thyroid cancers were defined as histologically confirmed cancers that were first suspected as a result of clinical and laboratory findings during the second to fourth screening examinations (2001–2007) and for which surgery was performed by December 2008. All individuals with a nodule of ≥ 10 mm in its largest dimension, or a nodule of 5–10 mm with ultrasound characteristics suggestive of malignancy (Stezhko et al. 2004
), were referred for fine-needle aspiration biopsy (FNAB) at the IEM. If an individual’s FNAB findings were diagnostic or suspicious for malignancy or follicular neoplasia, the person was referred for thyroid surgery. Of 855 individuals referred for FNAB during the second to fourth examinations, 637 (75%) complied, 38 (4%) did not comply, and for 180 (21%) the referral was canceled after a repeated ultrasound examination. Of the 109 individuals referred for thyroid surgery, 87 (80%) complied by December 2008. The International Pathology Panel, established in the framework of the Chernobyl Tissue Bank (2010)
, reviewed all histopathological diagnoses and confirmed all 65 cancers: 61 papillary (with one incidentally found microcarcinoma), 3 follicular, and 1 medullary thyroid cancer.
Dosimetric methods have been described elsewhere (Likhtarev et al. 2003
; Likhtarov et al. 2005
). Briefly, individual I-131 thyroid doses and their uncertainties were estimated from the combination of thyroid radioactivity measurements, data on dietary and lifestyle habits, and environmental transfer models using a Monte Carlo procedure with 1,000 realizations per individual (Likhtarev et al. 2003
). The distribution of 1,000 individual I-131 dose estimates was close to lognormal, with geometric SDs ranging from 1.6 to 5.0 for most cohort members (Likhtarev et al. 2003
). For the analysis, we used the arithmetic mean of each individual’s 1,000 realizations as the best estimate of I-131 dose. Because these dose estimates were derived from thyroid masses typical of iodine-sufficient populations (International Commission on Radiological Protection 1989
), we applied a correction coefficient to adjust them for thyroid masses typical of the Ukrainian population using data collected by the Sasakawa Memorial Health Foundation (for children 5–16 years of age) (Nikiforova et al. 1997
) and by the Ukrainian Radiation Protection Institute (for children < 5 years of age) (Likhtarev IA, personal communication). In the analysis cohort, the arithmetic means [geometric means (GMs)] of individual I-131 arithmetic means adjusted for thyroid mass typical of this region were 0.65 (0.20) Gy compared with the original means of 0.77 (0.26) Gy, respectively (Tronko et al. 2006a
). In general, dose estimates were negatively correlated with age at time of the accident. Individual thyroid dose estimates currently are available only for I-131 and not for other isotopes of iodine or cesium (Stezhko et al. 2004
). However, I-131 typically accounts for 90–95% of total thyroid dose (Likhtarev et al. 2003
; Stezhko et al. 2004
Statistical analysis. We counted person-years (PY) at risk from the date of the first screening examination to the date of thyroid surgery or to the date of last screening examination for those not operated upon. Data were cross-classified by age at exposure (from 0 to 18 years in 2-year intervals), attained age (from 12 to 40 years by 2-year intervals), dose estimates (< 0.05, 0.05–0.09, 0.1–0.29, 0.3–0.49, 0.5–0.69, 0.7–0.99, 1.0–1.49, 1.5–1.99, 2.0–2.49, 2.5–2.99, ≥ 3.0 Gy), and calendar time intervals (1998–2008 in 1-year intervals).
In addition, data were cross-classified by the following categorical variables reflecting status at the time of the first screening examination: oblast of residence (Zhytomyr, Kyiv, Chernihiv), type of residence (urban/rural), smoking status (yes/no), family history of thyroid disease (yes/no), presence of diffuse goiter on palpation (yes/no), and ultrasound-detected nodules (yes/no). Data also were cross-classified by sex, oblast of residence in 1986 (Zhytomyr, Kyiv, Chernihiv), and intake of iodine prophylaxis in May–June 1986 (yes/no). For each cross-classification cell, the number of observed thyroid cancers, PY, and PY-weighted means for continuous variables at the first screening examination (including TSH, ATPO, TG, thyroid volume, and urinary iodine) were computed.
We used Poisson regression models for grouped survival data to describe thyroid cancer incidence rates and to characterize radiation effects on these rates under relative and absolute risk models. Maximum likelihood parameter estimates, likelihood-based confidence intervals (CIs), and tests of independence or interaction were obtained using the AMFIT module of Epicure (Preston et al. 1993
). Statistical tests were two sided at an α-level of 0.05.
The linear excess relative risk (ERR) model has the form r0(x)*(1 + β*dose), where r0 is the baseline or background incidence rate, x is the vector of covariates that describes the background rate, and β is the parameter that measures unit increase in the ERR per gray. The linear excess absolute risk (EAR) model has the form r0(x) + β*dose, where β is the absolute excess rate of thyroid cancer per gray that adds to the background thyroid cancer rate. In both ERR and EAR models, background rate was modeled as an exponential function of sex, oblast of residence at the first screening examination, and continuous attained age without interaction terms. The selected covariates were known to be major risk factors for thyroid cancer in various populations and/or influenced the magnitude of estimated radiation risk in preliminary analyses. The ERR and EAR are not nested models and cannot be compared directly; however, it is reasonable to suggest that the fit with lower deviance is the “better” one given the same degrees of freedom.
To test departure from linearity, we fitted linear-exponential [r0(x)*(1 + β*dose*exp–γ*dose) or r0(x) + β*dose*exp–γ*dose)] and linear-
quadratic [r0(x)*(1 + β*dose + γ*dose2) or r0(x) + β*dose + γ*dose2)] models and compared their fit with the simple linear ERR and EAR models, respectively. A significant p-value at 1 degree of freedom (df) of likelihood ratio test comparing nested models indicates that the data were not consistent with linearity.
To test interaction or departure from the constant ERR or EAR models, we fitted the dose–response model with main effects only and compared its deviance with a model that also included dose–response parameters within J categories of factor of interest (sex, oblast, iodine prophylaxis, and diffuse goiter). A significant p-value at J – 1 df indicates that the effect of dose is not homogeneous across levels of the factor under consideration. Also, for continuous variables (age at exposure; attained age; time since exposure; and serum TG, TSH, and urinary iodine) we evaluated interaction with dose based on a 1 df test including an interaction term between continuous dose and factor under consideration.