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Health physics  2009;97(5):487-492.
Radiation dose estimates used in epidemiological studies are subject to many sources of uncertainty, and the error structure may be a complicated mixture of different types of error. Increasingly, efforts are being made to evaluate dosimetry uncertainties and to take account of them in statistical analyses. The impact of these uncertainties on dose response analyses depends on the magnitude and type of error. Errors that are independent from subject to subject (random errors) reduce statistical power for detecting a dose-response relationship, increase uncertainties in estimated risk coefficients, and may lead to underestimation of risk coefficients. The specific effects of random errors depend on whether the errors are “classical” or “Berkson.” Classical error can be thought of as error that arises from an imprecise measuring device, whereas Berkson error occurs when a single dose is used to represent a group of subjects (with varying true doses). Uncertainties in quantities that are common to some or all subjects are “shared” uncertainties. Such uncertainties increase the possibility of bias, and accounting for this possibility increases the length of confidence intervals. In studies that provide a direct evaluation of risk at low doses and dose rates, dosimetry errors are more likely to mask a true effect than to create a spurious one. In addition, classical errors and shared dosimetry uncertainties increase the potential for bias in estimated risks coefficients, but this potential may already be large due to the extreme vulnerability to confounding in studies involving very small relative risk.
PMCID: PMC4051435  PMID: 19820458
analysis; statistical; dosimetry; epidemiology; National Council on Radiation Protection and Measurements
2.  Impact of exposure measurement error in air pollution epidemiology: effect of error type in time-series studies 
Environmental Health  2011;10:61.
Two distinctly different types of measurement error are Berkson and classical. Impacts of measurement error in epidemiologic studies of ambient air pollution are expected to depend on error type. We characterize measurement error due to instrument imprecision and spatial variability as multiplicative (i.e. additive on the log scale) and model it over a range of error types to assess impacts on risk ratio estimates both on a per measurement unit basis and on a per interquartile range (IQR) basis in a time-series study in Atlanta.
Daily measures of twelve ambient air pollutants were analyzed: NO2, NOx, O3, SO2, CO, PM10 mass, PM2.5 mass, and PM2.5 components sulfate, nitrate, ammonium, elemental carbon and organic carbon. Semivariogram analysis was applied to assess spatial variability. Error due to this spatial variability was added to a reference pollutant time-series on the log scale using Monte Carlo simulations. Each of these time-series was exponentiated and introduced to a Poisson generalized linear model of cardiovascular disease emergency department visits.
Measurement error resulted in reduced statistical significance for the risk ratio estimates for all amounts (corresponding to different pollutants) and types of error. When modelled as classical-type error, risk ratios were attenuated, particularly for primary air pollutants, with average attenuation in risk ratios on a per unit of measurement basis ranging from 18% to 92% and on an IQR basis ranging from 18% to 86%. When modelled as Berkson-type error, risk ratios per unit of measurement were biased away from the null hypothesis by 2% to 31%, whereas risk ratios per IQR were attenuated (i.e. biased toward the null) by 5% to 34%. For CO modelled error amount, a range of error types were simulated and effects on risk ratio bias and significance were observed.
For multiplicative error, both the amount and type of measurement error impact health effect estimates in air pollution epidemiology. By modelling instrument imprecision and spatial variability as different error types, we estimate direction and magnitude of the effects of error over a range of error types.
PMCID: PMC3146396  PMID: 21696612
3.  Efficient measurement error correction with spatially misaligned data 
Biostatistics (Oxford, England)  2011;12(4):610-623.
Association studies in environmental statistics often involve exposure and outcome data that are misaligned in space. A common strategy is to employ a spatial model such as universal kriging to predict exposures at locations with outcome data and then estimate a regression parameter of interest using the predicted exposures. This results in measurement error because the predicted exposures do not correspond exactly to the true values. We characterize the measurement error by decomposing it into Berkson-like and classical-like components. One correction approach is the parametric bootstrap, which is effective but computationally intensive since it requires solving a nonlinear optimization problem for the exposure model parameters in each bootstrap sample. We propose a less computationally intensive alternative termed the “parameter bootstrap” that only requires solving one nonlinear optimization problem, and we also compare bootstrap methods to other recently proposed methods. We illustrate our methodology in simulations and with publicly available data from the Environmental Protection Agency.
PMCID: PMC3169665  PMID: 21252080
Environmental epidemiology; Environmental statistics; Exposure modeling; Kriging; Measurement error
4.  Non-parametric regression estimation from data contaminated by a mixture of Berkson and classical errors 
Estimation of a regression function is a well-known problem in the context of errors in variables, where the explanatory variable is observed with random noise. This noise can be of two types, which are known as classical or Berkson, and it is common to assume that the error is purely of one of these two types. In practice, however, there are many situations where the explanatory variable is contaminated by a mixture of the two errors. In such instances, the Berkson component typically arises because the variable of interest is not directly available and can only be assessed through a proxy, whereas the inaccuracy that is related to the observation of the latter causes an error of classical type. We propose a non-parametric estimator of a regression function from data that are contaminated by a mixture of the two errors. We prove consistency of our estimator, derive rates of convergence and suggest a data-driven implementation. Finite sample performance is illustrated via simulated and real data examples.
PMCID: PMC2733794  PMID: 19718280
Berkson errors; Deconvolution; Errors in variables; Kernel method; Measurement error; Orthogonal series; Radiation dosimetry; Smoothing parameter
5.  Measurement error caused by spatial misalignment in environmental epidemiology 
Biostatistics (Oxford, England)  2008;10(2):258-274.
In many environmental epidemiology studies, the locations and/or times of exposure measurements and health assessments do not match. In such settings, health effects analyses often use the predictions from an exposure model as a covariate in a regression model. Such exposure predictions contain some measurement error as the predicted values do not equal the true exposures. We provide a framework for spatial measurement error modeling, showing that smoothing induces a Berkson-type measurement error with nondiagonal error structure. From this viewpoint, we review the existing approaches to estimation in a linear regression health model, including direct use of the spatial predictions and exposure simulation, and explore some modified approaches, including Bayesian models and out-of-sample regression calibration, motivated by measurement error principles. We then extend this work to the generalized linear model framework for health outcomes. Based on analytical considerations and simulation results, we compare the performance of all these approaches under several spatial models for exposure. Our comparisons underscore several important points. First, exposure simulation can perform very poorly under certain realistic scenarios. Second, the relative performance of the different methods depends on the nature of the underlying exposure surface. Third, traditional measurement error concepts can help to explain the relative practical performance of the different methods. We apply the methods to data on the association between levels of particulate matter and birth weight in the greater Boston area.
PMCID: PMC2733173  PMID: 18927119
Air pollution; Measurement error; Predictions; Spatial misalignment
6.  Effect of measurement error on epidemiological studies of environmental and occupational exposures 
Random error (misclassification) in exposure measurements usually biases a relative risk, regression coefficient, or other effect measure towards the null value (no association). The most important exception is Berkson type error, which causes little or no bias. Berkson type error arises, in particular, due to use of group average exposure in place of individual values. Random error in exposure measurements, Berkson or otherwise, reduces the power of a study, making it more likely that real associations are not detected. Random error in confounding variables compromises the control of their effect, leaving residual confounding. Random error in a variable that modifies the effect of exposure on health--for example, an indicator of susceptibility--tends to diminish the observed modification of effect, but error in the exposure can create a supurious appearance of modification. Methods are available to correct for bias (but not generally power loss) due to measurement error, if information on the magnitude and type of error is available. These methods can be complicated to use, however, and should be used cautiously as "correction" can magnify confounding if it is present.
PMCID: PMC1757516  PMID: 9930084
7.  Impact of Uncertainties in Exposure Assessment on Estimates of Thyroid Cancer Risk among Ukrainian Children and Adolescents Exposed from the Chernobyl Accident 
PLoS ONE  2014;9(1):e85723.
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 (p = 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.
PMCID: PMC3906013  PMID: 24489667
8.  Comparison of the Influence on the Liver Function Between Thyroid Hormone Withdrawal and rh-TSH Before High-Dose Radioiodine Therapy in Patients with Well-Differentiated Thyroid Cancer 
An elevated thyroid stimulating hormone level (TSH) is essential to stimulate the uptake of radioiodine into thyroid remnants and metastases of thyroid cancer when a patient undergoes high-dose radioiodine therapy. Nowadays, recombinant human thyroid stimulating hormone (rh-TSH) is increasingly used instead of the classic method of thyroid hormone withdrawal (THW). However, beyond the therapeutic effects, clinical differences between the two methods have not yet been clearly demonstrated. The aim of this work was to investigate the effects of the two methods, especially on liver function.
We identified 143 evaluable patients who were further divided into two groups: THW and rh-TSH. We first reviewed the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, which were measured during the admission period for total thyroidectomy. We called these liver enzyme levels “base AST” and “base ALT.” We also assessed other chemistry profiles, including AST, ALT, total cholesterol, LDL cholesterol, alkaline phosphatase (ALP), total bilirubin (TB), and triglyceride (TG), which were measured on admission day for high-dose radioiodine therapy. We called these liver enzyme levels “follow-up AST” and “follow-up ALT.” We compared the changes in base and follow-up liver enzyme levels and the other chemistry profiles between the two groups.
The base AST and base ALT levels of the two groups were within normal range, and there was no significant difference between the two groups. In contrast to these base liver enzyme levels, follow-up liver enzyme levels between the two groups showed significant differences. Patients in the THW group had higher follow-up AST and ALT levels than did the rh-TSH group. Patients in the THW group also had higher levels of total cholesterol and LDL cholesterol than did the patients in the rh-TSH group. However there were no statistically significant differences in ALP, total bilirubin, and triglyceride levels between the two groups.
In this retrospective analysis of liver function, the use of rh-TSH for high-dose radioiodine therapy had less of an effect on liver function and cholesterol levels than dose thyroid hormone withdrawal. This suggests that rh-TSH can be used effectively and safely especially for patients with metabolic syndrome.
PMCID: PMC4042988  PMID: 24900040
Thyroid cancer; High-dose radioiodine therapy; Recombinant human TSH; Thyroid hormone withdrawal; Liver function
9.  Thyroid doses for evacuees from the Fukushima nuclear accident 
Scientific Reports  2012;2:507.
A primary health concern among residents and evacuees in affected areas immediately after a nuclear accident is the internal exposure of the thyroid to radioiodine, particularly I-131, and subsequent thyroid cancer risk. In Japan, the natural disasters of the earthquake and tsunami in March 2011 destroyed an important function of the Fukushima Daiichi Nuclear Power Plant (F1-NPP) and a large amount of radioactive material was released to the environment. Here we report for the first time extensive measurements of the exposure to I-131 revealing I-131 activity in the thyroid of 46 out of the 62 residents and evacuees measured. The median thyroid equivalent dose was estimated to be 4.2 mSv and 3.5 mSv for children and adults, respectively, much smaller than the mean thyroid dose in the Chernobyl accident (490 mSv in evacuees). Maximum thyroid doses for children and adults were 23 mSv and 33 mSv, respectively.
PMCID: PMC3395030  PMID: 22792439
Health physics  2010;99(1):1-16.
A population-based case-control study of thyroid cancer was carried out in contaminated regions of Belarus and Russia among persons who were exposed during childhood and adolescence to fallout from the Chernobyl accident. For each study subject, individual thyroid doses were reconstructed for the following pathways of exposure: (1) intake of 131I via inhalation and ingestion; (2) intake of short-lived radioiodines (132I, 133I, and 135I) and radiotelluriums (131mTe, 132Te) via inhalation and ingestion; (3) external dose from radionuclides deposited on the ground; and (4) ingestion of 134Cs and 137Cs. A series of intercomparison exercises validated the models used for reconstruction of average doses to populations of specific age groups as well as of individual doses. Median thyroid doses from all factors for study subjects were estimated to be 0.37 and 0.034 Gy in Belarus and Russia, respectively. The highest individual thyroid doses among the subjects were 10.2 Gy in Belarus and 5.3 Gy in Russia. Iodine-131 intake was the main pathway for thyroid exposure. Estimated doses from short-lived radioiodines and radiotelluriums ranged up to 0.53 Gy. Reconstructed individual thyroid doses from external exposure ranged up to 0.1 Gy, while those from internal exposure due to ingested cesium did not exceed 0.05 Gy. The uncertainty of the reconstructed individual thyroid doses, characterized by the geometric standard deviation, varies from 1.7 to 4.0 with a median of 2.2.
PMCID: PMC2885044  PMID: 20539120
Chernobyl; radioiodine; dose reconstruction; thyroid
11.  I-131 Dose Response for Incident Thyroid Cancers in Ukraine Related to the Chornobyl Accident 
Environmental Health Perspectives  2011;119(7):933-939.
Background: Current knowledge about Chornobyl-related thyroid cancer risks comes from ecological studies based on grouped doses, case–control studies, and studies of prevalent cancers.
Objective: To address this limitation, we evaluated the dose–response relationship for incident thyroid cancers using measurement-based individual iodine-131 (I-131) thyroid dose estimates in a prospective analytic cohort study.
Methods: The cohort consists of individuals < 18 years of age on 26 April 1986 who resided in three contaminated oblasts (states) of Ukraine and underwent up to four thyroid screening examinations between 1998 and 2007 (n = 12,514). Thyroid doses of I-131 were estimated based on individual radioactivity measurements taken within 2 months after the accident, environmental transport models, and interview data. Excess radiation risks were estimated using Poisson regression models.
Results: Sixty-five incident thyroid cancers were diagnosed during the second through fourth screenings and 73,004 person-years (PY) of observation. The dose–response relationship was consistent with linearity on relative and absolute scales, although the excess relative risk (ERR) model described data better than did the excess absolute risk (EAR) model. The ERR per gray was 1.91 [95% confidence interval (CI), 0.43–6.34], and the EAR per 104 PY/Gy was 2.21 (95% CI, 0.04–5.78). The ERR per gray varied significantly by oblast of residence but not by time since exposure, use of iodine prophylaxis, iodine status, sex, age, or tumor size.
Conclusions: I-131–related thyroid cancer risks persisted for two decades after exposure, with no evidence of decrease during the observation period. The radiation risks, although smaller, are compatible with those of retrospective and ecological post-Chornobyl studies.
PMCID: PMC3222994  PMID: 21406336
Chernobyl nuclear accident; Chornobyl, Ukraine, 1986; dose–response relationship; incidence, thyroid neoplasms/epidemiology; iodine; radioactive; radiation
12.  Thyroid nodules, polymorphic variants in DNA repair and RET-related genes, and interaction with ionizing radiation exposure from nuclear tests in Kazakhstan 
Radiation research  2009;171(1):77-88.
Risk factors for thyroid cancer remain largely unknown except for ionizing radiation exposure during childhood and a history of benign thyroid nodules. Because thyroid nodules are more common than thyroid cancers and are associated with thyroid cancer risk, we evaluated several polymorphisms potentially relevant to thyroid tumors and assessed interaction with ionizing radiation exposure to the thyroid gland. Thyroid nodules were detected in 1998 by ultrasound screening of 2997 persons who lived near the Semipalatinsk nuclear test site in Kazakhstan when they were children (1949-62). Cases with thyroid nodules (n=907) were frequency matched (1:1) to those without nodules by ethnicity (Kazakh or Russian), gender, and age at screening. Thyroid gland radiation doses were estimated from fallout deposition patterns, residence history, and diet. We analyzed 23 polymorphisms in 13 genes and assessed interaction with ionizing radiation exposure using likelihood ratio tests (LRT). Elevated thyroid nodule risks were associated with the minor alleles of RET S836S (rs1800862, p = 0.03) and GFRA1 -193C>G (rs not assigned, p = 0.05) and decreased risk with XRCC1 R194W (rs1799782, p-trend = 0.03) and TGFB1 T263I (rs1800472, p = 0.009). Similar patterns of association were observed for a small number of papillary thyroid cancers (n=25). Ionizing radiation exposure to the thyroid gland was associated with significantly increased risk of thyroid nodules (age and gender adjusted excess odds ratio/Gy = 0.30, 95% confidence interval 0.05-0.56), with evidence for interaction by genotype found for XRCC1 R194W (LRT p value = 0.02). Polymorphisms in RET signaling, DNA repair, and proliferation genes may be related to risk of thyroid nodules, consistent with some previous reports on thyroid cancer. Borderline support for gene-radiation interaction was found for a variant in XRCC1, a key base excision repair protein. Other pathways, such as genes in double strand break repair, apoptosis, and genes related to proliferation should also be pursued.
PMCID: PMC2875679  PMID: 19138047
Thyroid nodules; single nucleotide polymorphisms; epidemiology; thyroid cancer; ionizing radiation; interaction
13.  Bayesian adjustment for measurement error in continuous exposures in an individually matched case-control study 
In epidemiological studies explanatory variables are frequently subject to measurement error. The aim of this paper is to develop a Bayesian method to correct for measurement error in multiple continuous exposures in individually matched case-control studies. This is a topic that has not been widely investigated. The new method is illustrated using data from an individually matched case-control study of the association between thyroid hormone levels during pregnancy and exposure to perfluorinated acids. The objective of the motivating study was to examine the risk of maternal hypothyroxinemia due to exposure to three perfluorinated acids measured on a continuous scale. Results from the proposed method are compared with those obtained from a naive analysis.
Using a Bayesian approach, the developed method considers a classical measurement error model for the exposures, as well as the conditional logistic regression likelihood as the disease model, together with a random-effect exposure model. Proper and diffuse prior distributions are assigned, and results from a quality control experiment are used to estimate the perfluorinated acids' measurement error variability. As a result, posterior distributions and 95% credible intervals of the odds ratios are computed. A sensitivity analysis of method's performance in this particular application with different measurement error variability was performed.
The proposed Bayesian method to correct for measurement error is feasible and can be implemented using statistical software. For the study on perfluorinated acids, a comparison of the inferences which are corrected for measurement error to those which ignore it indicates that little adjustment is manifested for the level of measurement error actually exhibited in the exposures. Nevertheless, a sensitivity analysis shows that more substantial adjustments arise if larger measurement errors are assumed.
In individually matched case-control studies, the use of conditional logistic regression likelihood as a disease model in the presence of measurement error in multiple continuous exposures can be justified by having a random-effect exposure model. The proposed method can be successfully implemented in WinBUGS to correct individually matched case-control studies for several mismeasured continuous exposures under a classical measurement error model.
PMCID: PMC3120807  PMID: 21569573
14.  Use of Pre-Ablation Radioiodine-131 Scan to Assess the Impact of Surgical Volume and Specialisation following Thyroidectomy for Differentiated Thyroid Carcinoma 
European Thyroid Journal  2013;2(4):275-281.
We evaluated the relationship between thyroid remnant size following thyroidectomy for differentiated thyroid carcinoma and surgical volume and specialisation by assessing pre-ablation radioiodine-131 (131I) thyroid bed uptake (TBU) scanning as a surrogate for residual thyroid tissue.
We analysed data of 651 patients in our thyroid cancer database. Patients' data were included if the following criteria were met: (1) diagnosis of differentiated thyroid carcinoma, (2) total or near-total thyroidectomy, (3) pre-ablation 131I scan prior to radioiodine ablation (RAI), (4) no distant metastasis, and (5) >3,000 MBq ablative dose of 131I. 131I diagnostic whole-body scans and measurement of thyroglobulin levels were carried out 3-9 months after RAI. 305 patients were included in the final analysis.
Four endocrine, 19 otolaryngology and 25 general surgeons performed thyroidectomies with median pre-ablation 131I TBU values of 1.0, 1.8 and 2.9%, respectively (p = 0.0031). There was a statistically significant relationship between number of thyroidectomies performed and median pre-ablation 131I TBU values up to the optimal number of 11 operations beyond which there was no further significant difference between surgeons. There were differences in remnant size between endocrine and general surgeons (p = 0.001), otolaryngology and general surgeons (p = 0.023) but not between endocrine and otolaryngology surgeons (p = 0.167).
Using the pre-ablation 131I uptake scan as a surrogate for thyroid remnant quantification following thyroidectomy demonstrates the relationship between the surgical volume and size of thyroid remnant. The study also demonstrated beneficial effects of specialisation with specialist surgeons achieving the smallest thyroid remnant.
PMCID: PMC3923598  PMID: 24783059
Thyroid cancer; Surgeon volume; Thyroid remnant; 
Pre-ablation radioiodine scan; Surgical specialisation

15.  Mathematical modeling of a survey-meter used to measure radioactivity in human thyroids: Monte Carlo calculations of the device response and uncertainties 
This paper presents results of Monte Carlo modeling of the SRP-68-01 survey meter used to measure exposure rates near the thyroid glands of persons exposed to radioactivity following the Chernobyl accident. This device was not designed to measure radioactivity in humans. To estimate the uncertainty associated with the measurement results, a mathematical model of the SRP-68-01 survey meter was developed and verified. A Monte Carlo method of numerical simulation of radiation transport has been used to calculate the calibration factor for the device and evaluate its uncertainty. The SRP-68-01 survey meter scale coefficient, an important characteristic of the device, was also estimated in this study. The calibration factors of the survey meter were calculated for 131I, 132I, 133I, and 135I content in the thyroid gland for six age groups of population: newborns; children aged 1 yr, 5 yr, 10 yr, 15 yr; and adults. A realistic scenario of direct thyroid measurements with an “extended” neck was used to calculate the calibration factors for newborns and one-year-olds. Uncertainties in the device calibration factors due to variability of the device scale coefficient, variability in thyroid mass and statistical uncertainty of Monte Carlo method were evaluated. Relative uncertainties in the calibration factor estimates were found to be from 0.06 for children aged 1 yr to 0.1 for 10-yr and 15-yr children. The positioning errors of the detector during measurements deviate mainly in one direction from the estimated calibration factors. Deviations of the device position from the proper geometry of measurements were found to lead to overestimation of the calibration factor by up to 24 percent for adults and up to 60 percent for 1-yr children. The results of this study improve the estimates of 131I thyroidal content and, consequently, thyroid dose estimates that are derived from direct thyroid measurements performed in Belarus shortly after the Chernobyl accident.
PMCID: PMC3430078  PMID: 22245289
Chernobyl; Thyroid; Measurement; Survey meter; Monte Carlo
16.  Thyroid cancer risk in Belarus among children and adolescents exposed to radioiodine after the Chornobyl accident 
British Journal of Cancer  2010;104(1):181-187.
Previous studies showed an increased risk of thyroid cancer among children and adolescents exposed to radioactive iodines released after the Chornobyl (Chernobyl) accident, but the effects of screening, iodine deficiency, age at exposure and other factors on the dose–response are poorly understood.
We screened 11 970 individuals in Belarus aged 18 years or younger at the time of the accident who had estimated 131I thyroid doses based on individual thyroid activity measurements and dosimetric data from questionnaires. The excess odds ratio per gray (EOR/Gy) was modelled using linear and linear–exponential functions.
For thyroid doses <5 Gy, the dose–response was linear (n=85; EOR/Gy=2.15, 95% confidence interval: 0.81–5.47), but at higher doses the excess risk fell. The EOR/Gy was significantly increased among those with prior or screening-detected diffuse goiter, and larger for men than women, and for persons exposed before age 5 than those exposed between 5 and 18 years, although not statistically significant. A somewhat higher EOR/Gy was estimated for validated pre-screening cases.
10–15 years after the Chornobyl accident, thyroid cancer risk was significantly increased among individuals exposed to fallout as children or adolescents, but the risk appeared to be lower than in other Chornobyl studies and studies of childhood external irradiation.
PMCID: PMC3039791  PMID: 21102590
thyroid neoplasms; iodine radioisotopes; Chernobyl nuclear accident; risk; iodine deficiency
17.  Asymmetric breast uptake of radioiodine in a patient with thyroid malignancy: metastases or not? 
Various physiological processes can cause potentially misleading appearances in radioiodine whole body scans; proper understanding of the causes of these can therefore obviate diagnostic errors. Whole-body radioiodine scintigraphy with I131 or I123 is an accurate form of imaging used for management of differentiated thyroid carcinoma. Following thyroidectomy, any residual thyroid tissue or metastatic disease is ablated with high dose I131 and diagnostic images are acquired, demonstrating residual thyroid tissue and metastatic disease. However, atypical physiological uptake of I131 can simulate metastases.
PMCID: PMC2408632  PMID: 18515780
18.  Item Response Theory and Health Outcomes Measurement in the 21st Century 
Medical care  2000;38(9 Suppl):II28-II42.
Item response theory (IRT) has a number of potential advantages over classical test theory in assessing self-reported health outcomes. IRT models yield invariant item and latent trait estimates (within a linear transformation), standard errors conditional on trait level, and trait estimates anchored to item content. IRT also facilitates evaluation of differential item functioning, inclusion of items with different response formats in the same scale, and assessment of person fit and is ideally suited for implementing computer adaptive testing. Finally, IRT methods can be helpful in developing better health outcome measures and in assessing change over time. These issues are reviewed, along with a discussion of some of the methodological and practical challenges in applying IRT methods.
PMCID: PMC1815384  PMID: 10982088
item response theory; health outcomes; differential item functioning; computer adaptive testing
19.  Berkson’s bias, selection bias, and missing data 
Epidemiology (Cambridge, Mass.)  2012;23(1):159-164.
While Berkson’s bias is widely recognized in the epidemiologic literature, it remains underappreciated as a model of both selection bias and bias due to missing data. Simple causal diagrams and 2×2 tables illustrate how Berkson’s bias connects to collider bias and selection bias more generally, and show the strong analogies between Berksonian selection bias and bias due to missing data. In some situations, considerations of whether data are missing at random or missing not at random is less important than the causal structure of the missing-data process. While dealing with missing data always relies on strong assumptions about unobserved variables, the intuitions built with simple examples can provide a better understanding of approaches to missing data in real-world situations.
PMCID: PMC3237868  PMID: 22081062
20.  Hypothyroxinemia Induced by Mild Iodine Deficiency Deregulats Thyroid Proteins during Gestation and Lactation in Dams 
The main object of the present study was to explore the effect on thyroidal proteins following mild iodine deficiency (ID)-induced maternal hypothyroxinemia during pregnancy and lactation. In the present study, we established a maternal hypothyroxinemia model in female Wistar rats by using a mild ID diet. Maternal thyroid iodine content and thyroid weight were measured. Expressions of thyroid-associated proteins were analyzed. The results showed that the mild ID diet increased thyroid weight, decreased thyroid iodine content and increased expressions of thyroid transcription factor 1, paired box gene 8 and Na+/I− symporter on gestational day (GD) 19 and postpartum days (PN) 21 in the maternal thyroid. Moreover, the up-regulated expressions of type 1 iodothyronine deiodinase (DIO1) and type 2 iodothyronine deiodinase (DIO2) were detected in the mild ID group on GD19 and PN21. Taken together, our data indicates that during pregnancy and lactation, a maternal mild ID could induce hypothyroxinemia and increase the thyroidal DIO1 and DIO2 levels.
PMCID: PMC3774435  PMID: 23917811
mild iodine deficiency; hypothyroxinemia; gestation; lactation; thyroid
21.  A Steep Radioiodine Dose Response Scalable to Humans in Sodium Iodide Symporter (NIS) Mediated Radiovirotherapy for Prostate Cancer 
Cancer gene therapy  2012;19(12):839-844.
The sodium iodide symporter (NIS) directs the uptake and concentration of iodide in thyroid cells. We have extended the use of NIS-mediated radioiodine therapy to prostate cancer. We have developed a prostate tumor specific conditionally replicating adenovirus (CRAd) that expresses hNIS (Ad5PB_RSV-NIS). For radiovirotherapy to be effective in humans, the radioiodine dose administered in the pre-clinical animal model should scale to the range of acceptable doses in humans. We performed 131I dose-response experiments aiming to determine the dose required in mice to achieve efficient radiovirotherapy. Efficacy was determined by measuring tumor growth and survival times. We observed that individual tumors display disparate growth rates which preclude averaging within a treatment modality indicating heterogeneity of growth rate. We further show that a statistic and stochastic approach must be used when comparing the effect of an anti-cancer therapy on a cohort of tumors. Radiovirotherapy improves therapeutic value over virotherapy alone by slowing the rate of tumor growth in a more substantial manner leading to an increase in survival time. We also show that the radioiodine doses needed to achieve this increase scaled well within the current doses used for treatment of thyroid cancer in humans.
PMCID: PMC3499676  PMID: 23037808
prostate cancer; probasin; adenovirus; sodium iodide symporter; virotherapy; gene therapy; allometry
22.  General Error Analysis in the Relationship between Free Thyroxine and Thyrotropin and Its Clinical Relevance 
Background. This treatise investigates error sources in measurements applicable to the hypothalamus-pituitary-thyroid (HPT) system of analysis for homeostatic set point computation. The hypothalamus-pituitary transfer characteristic (HP curve) describes the relationship between plasma free thyroxine [FT4] and thyrotropin [TSH]. Objective. We define the origin, types, causes, and effects of errors that are commonly encountered in TFT measurements and examine how we can interpret these to construct a reliable HP function for set point establishment. Design and Methods. The error sources in the clinical measurement procedures are identified and analyzed in relation to the constructed HP model. Results. The main sources of measurement and interpretation uncertainties are (1) diurnal variations in [TSH], (2) TFT measurement variations influenced by timing of thyroid medications, (3) error sensitivity in ranges of [TSH] and [FT4] (laboratory assay dependent), (4) rounding/truncation of decimals in [FT4] which in turn amplify curve fitting errors in the [TSH] domain in the lower [FT4] range, (5) memory effects (rate-independent hysteresis effect). Conclusions. When the main uncertainties in thyroid function tests (TFT) are identified and analyzed, we can find the most acceptable model space with which we can construct the best HP function and the related set point area.
PMCID: PMC3780511  PMID: 24082916
23.  Effectiveness of L-thyroxine treatment on TSH suppression during pregnancy in patients with a history of thyroid carcinoma after total thyroidectomy and radioiodine ablation 
Radiology and Oncology  2012;46(2):160-165.
There are scarce data about the optimal increase of L-thyroxine dose during pregnancy in patients with a history of thyroid carcinoma. The first aim of the study was to find out if routine therapeutic measures enable adequate TSH suppression in pregnancy. The other aim was to find out the optimal dose of L-thyroxine for TSH suppression in pregnant women.
Patients and methods.
In this retrospective observational study, we analysed 36 pregnancies of 32 women with a history of thyroid carcinoma. Before pregnancy, all of them underwent total thyroidectomy and radioiodine ablation of thyroid remnant, and they were on suppressive doses of L-thyroxine. Thyroid function tests were obtained before, during and after pregnancy.
Mean L-thyroxine dose before pregnancy, in the first, second and, third trimester and after delivery was 149, 147, 155, 165 and 158 micrograms daily, respectively. TSH concentration remained suppressed in 9 pregnancies, it was within normal range in 22 and elevated in 5 pregnancies. The mean dose of L-thyroxine in patients with suppressed TSH before pregnancy, in the first, second and, third trimester and after delivery was 154, 154, 164, 160 and 161 micrograms daily, respectively. When the dose had to be changed, the mean increase of the dose was 31.5 micrograms daily.
The range of changes in TSH concentration during pregnancy in the patients who have been on suppressive L-thyroxine therapy before conception is quite wide. TSH was adequately suppressed in only 25% of pregnancies. The dose of L-thyroxine in patients with suppressed TSH in the first, second and third trimester was 154, 164 and 160 micrograms daily, respectively.
PMCID: PMC3472936  PMID: 23077453
pregnancy; TSH suppression; L-thyroxine; thyroid carcinoma
24.  Application of a Repeat-Measure Biomarker Measurement Error Model to 2 Validation Studies: Examination of the Effect of Within-Person Variation in Biomarker Measurements 
American Journal of Epidemiology  2011;173(6):683-694.
Repeat-biomarker measurement error models accounting for systematic correlated within-person error can be used to estimate the correlation coefficient (ρ) and deattenuation factor (λ), used in measurement error correction. These models account for correlated errors in the food frequency questionnaire (FFQ) and the 24-hour diet recall and random within-person variation in the biomarkers. Failure to account for within-person variation in biomarkers can exaggerate correlated errors between FFQs and 24-hour diet recalls. For 2 validation studies, ρ and λ were calculated for total energy and protein density. In the Automated Multiple-Pass Method Validation Study (n = 471), doubly labeled water (DLW) and urinary nitrogen (UN) were measured twice in 52 adults approximately 16 months apart (2002–2003), yielding intraclass correlation coefficients of 0.43 for energy (DLW) and 0.54 for protein density (UN/DLW). The deattenuated correlation coefficient for protein density was 0.51 for correlation between the FFQ and the 24-hour diet recall and 0.49 for correlation between the FFQ and the biomarker. Use of repeat-biomarker measurement error models resulted in a ρ of 0.42. These models were similarly applied to the Observing Protein and Energy Nutrition Study (1999–2000). In conclusion, within-person variation in biomarkers can be substantial, and to adequately assess the impact of correlated subject-specific error, this variation should be assessed in validation studies of FFQs.
PMCID: PMC3105260  PMID: 21343245
bias (epidemiology); biological markers; data collection; energy intake; nutrition assessment; proteins; validation studies
25.  Validation of 131I ecological transfer models and thyroid dose assessments using Chernobyl fallout data from the Plavsk district, Russia 
Within the project “Environmental Modelling for Radiation Safety” (EMRAS) organized by the IAEA in 2003 experimental data of 131I measurements following the Chernobyl accident in the Plavsk district of Tula region, Russia were used to validate the calculations of some radioecological transfer models. Nine models participated in the inter-comparison. Levels of 137Cs soil contamination in all the settlements and 131I/137Cs isotopic ratios in the depositions in some locations were used as the main input information. 370 measurements of 131I content in thyroid of townspeople and villagers, and 90 measurements of 131I concentration in milk were used for validation of the model predictions.
A remarkable improvement in models performance comparing with previous inter-comparison exercise was demonstrated. Predictions of the various models were within a factor of three relative to the observations, discrepancies between the estimates of average doses to thyroid produced by most participant not exceeded a factor of ten.
PMCID: PMC2791700  PMID: 19783331
Chernobyl accident; iodine-131; environment modeling; models validation; population; thyroid dose

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