Impact of Uncertainties in Exposure Assessment on Estimates of Thyroid Cancer Risk among Ukrainian Children and Adolescents Exposed from the Chernobyl Accident

<div><p>The 1986 accident at the Chernobyl nuclear power plant remains the most serious nuclear accident in history, and excess thyroid cancers, particularly among those exposed to releases of iodine-131 remain the best-documented sequelae. Failure to take dose-measurement error into account can lead to bias in assessments of dose-response slope. Although risks in the Ukrainian-US thyroid screening study have been previously evaluated, errors in dose assessments have not been addressed hitherto. Dose-response patterns were examined in a thyroid screening prevalence cohort of 13,127 persons aged <18 at the time of the accident who were resident in the most radioactively contaminated regions of Ukraine. We extended earlier analyses in this cohort by adjusting for dose error in the recently developed TD-10 dosimetry. Three methods of statistical correction, via two types of regression calibration, and Monte Carlo maximum-likelihood, were applied to the doses that can be derived from the ratio of thyroid activity to thyroid mass. The two components that make up this ratio have different types of error, Berkson error for thyroid mass and classical error for thyroid activity. The first regression-calibration method yielded estimates of excess odds ratio of 5.78 Gy⁻¹ (95% CI 1.92, 27.04), about 7% higher than estimates unadjusted for dose error. The second regression-calibration method gave an excess odds ratio of 4.78 Gy⁻¹ (95% CI 1.64, 19.69), about 11% lower than unadjusted analysis. The Monte Carlo maximum-likelihood method produced an excess odds ratio of 4.93 Gy⁻¹ (95% CI 1.67, 19.90), about 8% lower than unadjusted analysis. There are borderline-significant (<i>p = </i>0.101–0.112) indications of downward curvature in the dose response, allowing for which nearly doubled the low-dose linear coefficient. In conclusion, dose-error adjustment has comparatively modest effects on regression parameters, a consequence of the relatively small errors, of a mixture of Berkson and classical form, associated with thyroid dose assessment.</p></div

Distribution of the geometric standard deviation (GSD) of errors associated with assessments of thyroid activity GSD as a function of TD-10 thyroid dose.

<p>Low dose range.</p

Variation of excess relative risk with age at the time of the accident (using 1^st regression calibration method, adapted from Kukush <i>et al.</i>[13]).

<p>Other details as for <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0085723#pone-0085723-g004" target="_blank">Figure 4</a>.</p

Analysis of curvature in fits of EOR model (2) with or without adjustment for dose errors using regression calibration, for TD-10 doses.

<p>All models have underlying rates adjusted for age (treated categorically) and gender. Unless otherwise stated all CI are profile-likelihood based.</p>a<p>unless otherwise stated all <i>p</i>-values refer to the improvement in fit of the current row in the Table with that of the model fitted in the row immediately above.</p>b<p><i>p</i>-value of improvement in fit compared with a model with no dose terms.</p

Dose response (+95 CI) for thyroid cancer in relation to TD-10 unadjusted dose, and regression-calibration-adjusted dose (using 1^st method, adapted from Kukush <i>et al.</i>[13]).

<p>The models are adjusted for age (treated categorically) and gender in the baseline. Dashed red line shows odds ratio  = 1.</p

Results of fits of optimal excess relative risk model (2) (maximum likelihood fits and 95% profile CI), all based on TD-10 dose estimates adjusted using 1^st regression calibration method (of Kukush <i>et al.</i>). All models have underlying rates adjusted for age (treated categorically) and gender. Parameters are given (with 95% CI), with associated <i>p</i>-values.^a Unless otherwise stated all CI are profile-likelihood based.

a<p>Unless otherwise stated all <i>p</i>-values refer to improvement in fit of model immediately above indicated one in the Table.</p>b<p><i>p</i>-value for improvement in fit over null model (without linear dose term).</p>c<p><i>p</i>-value for improvement in fit over model 2, linear-exponential in dose.</p>d<p>indications of lack of convergence.</p>e<p>Wald-based CI.</p

Histopathological features of papillary thyroid carcinomas detected during four screening examinations of a Ukrainian-American cohort

BACKGROUND: There are limited data on the histopathology of papillary thyroid carcinomas (PTCs) diagnosed in irradiated populations. We evaluated the associations between iodine-131 dose and the histopathological characteristics of post-Chernobyl PTCs, the changes in these characteristics over time, and their associations with selected somatic mutations. METHODS: This study included 115 PTCs diagnosed in a Ukrainian-American cohort (n=13 243) during prescreening and four successive thyroid screenings. Of these PTCs, 65 were subjected to somatic mutation profiling. All individuals were <18 years at the time of the Chernobyl accident and had direct thyroid radioactivity measurements. Statistical analyses included multivariate linear and logistic regression. RESULTS: We identified a borderline significant linear-quadratic association (P=0.063) between iodine-131 dose and overall tumour invasiveness (presence of extrathyroidal extension, lymphatic/vascular invasion, and regional or distant metastases). Irrespective of dose, tumours with chromosomal rearrangements were more likely to have lymphatic/vascular invasion than tumours without chromosomal rearrangements (P=0.020) or tumours with BRAF or RAS point mutations (P=0.008). Controlling for age, there were significant time trends in decreasing tumour size (P<0.001), the extent of lymphatic/vascular invasion (P=0.005), and overall invasiveness (P=0.026). CONCLUSIONS: We determined that the invasive properties of PTCs that develop in iodine-131-exposed children may be associated with radiation dose. In addition, based on a subset of cases, tumours with chromosomal rearrangements appear to have a more invasive phenotype. The increase in small, less invasive PTCs over time is a consequence of repeated screening examinations