[Show abstract][Hide abstract] ABSTRACT: The Thyrotoxicosis Therapy Follow-up Study (TTFUS) is comprised of 35,593 hyperthyroid patients treated from the mid-1940s through the mid-1960s. One objective of the TTFUS was to evaluate the long-term effects of high-dose iodine-131 ((131)I) treatment (1-4). In the TTFUS cohort, 23,020 patients were treated with (131)I, including 21,536 patients with Graves disease (GD), 1,203 patients with toxic nodular goiter (TNG) and 281 patients with unknown disease. The study population constituted the largest group of hyperthyroid patients ever examined in a single health risk study. The average number (±1 standard deviation) of (131)I treatments per patient was 1.7 ± 1.4 for the GD patients and 2.1 ± 2.1 for the TNG patients. The average total (131)I administered activity was 380 ± 360 MBq for GD patients and 640 ± 550 MBq for TNG patients. In this work, a biokinetic model for iodine was developed to derive organ residence times and to reconstruct the radiation-absorbed doses to the thyroid gland and to other organs resulting from administration of (131)I to hyperthyroid patients. Based on (131)I data for a small, kinetically well-characterized sub-cohort of patients, multivariate regression equations were developed to relate the numbers of disintegrations of (131)I in more than 50 organs and tissues to anatomical (thyroid mass) and clinical (percentage thyroid uptake and pulse rate) parameters. These equations were then applied to estimate the numbers of (131)I disintegrations in the organs and tissues of all other hyperthyroid patients in the TTFUS who were treated with (131)I. The reference voxel phantoms adopted by the International Commission on Radiological Protection (ICRP) were then used to calculate the absorbed doses in more than 20 organs and tissues of the body. As expected, the absorbed doses were found to be highest in the thyroid (arithmetic means of 120 and 140 Gy for GD and TNG patients, respectively). Absorbed doses in organs other than the thyroid were much smaller, with arithmetic means of 1.6 Gy, 1.5 Gy and 0.65 Gy for esophagus, thymus and salivary glands, respectively. The arithmetic mean doses to all other organs and tissues were more than 100 times less than those to the thyroid gland. To our knowledge, this work represents the most comprehensive study to date of the doses received by persons treated with (131)I for hyperthyroidism.
Full-text · Article · Nov 2015 · Radiation Research
[Show abstract][Hide abstract] ABSTRACT: Background
The excess incidence of thyroid cancer in Ukraine and Belarus observed a few years after the Chernobyl accident is considered to be largely the result of 131I released from the reactor. Although the Belarus thyroid cancer prevalence data has been previously analyzed, no account was taken of dose measurement error.
We examined dose-response patterns in a thyroid screening prevalence cohort of 11,732 persons aged under 18 at the time of the accident, diagnosed during 1996–2004, who had direct thyroid 131I activity measurement, and were resident in the most radio-actively contaminated regions of Belarus. Three methods of dose-error correction (regression calibration, Monte Carlo maximum likelihood, Bayesian Markov Chain Monte Carlo) were applied.
There was a statistically significant (p<0.001) increasing dose-response for prevalent thyroid cancer, irrespective of regression-adjustment method used. Without adjustment for dose errors the excess odds ratio was 1.51 Gy-1 (95% CI 0.53, 3.86), which was reduced by 13% when regression-calibration adjustment was used, 1.31 Gy-1 (95% CI 0.47, 3.31). A Monte Carlo maximum likelihood method yielded an excess odds ratio of 1.48 Gy-1 (95% CI 0.53, 3.87), about 2% lower than the unadjusted analysis. The Bayesian method yielded a maximum posterior excess odds ratio of 1.16 Gy-1 (95% BCI 0.20, 4.32), 23% lower than the unadjusted analysis. There were borderline significant (p = 0.053–0.078) indications of downward curvature in the dose response, depending on the adjustment methods used. There were also borderline significant (p = 0.102) modifying effects of gender on the radiation dose trend, but no significant modifying effects of age at time of accident, or age at screening as modifiers of dose response (p>0.2).
In summary, the relatively small contribution of unshared classical dose error in the current study results in comparatively modest effects on the regression parameters.
[Show abstract][Hide abstract] ABSTRACT: When conducting a meta-analysis of a continuous outcome, estimated means and standard deviations from the selected studies are required in order to obtain an overall estimate of the mean effect and its confidence interval. If these quantities are not directly reported in the publications, they must be estimated from other reported summary statistics, such as the median, the minimum, the maximum, and quartiles.
We propose a simulation-based estimation approach using the Approximate Bayesian Computation (ABC) technique for estimating mean and standard deviation based on various sets of summary statistics found in published studies. We conduct a simulation study to compare the proposed ABC method with the existing methods of Hozo et al. (2005), Bland (2015), and Wan et al. (2014).
In the estimation of the standard deviation, our ABC method performs better than the other methods when data are generated from skewed or heavy-tailed distributions. The corresponding average relative error (ARE) approaches zero as sample size increases. In data generated from the normal distribution, our ABC performs well. However, the Wan et al. method is best for estimating standard deviation under normal distribution. In the estimation of the mean, our ABC method is best regardless of assumed distribution.
ABC is a flexible method for estimating the study-specific mean and standard deviation for meta-analysis, especially with underlying skewed or heavy-tailed distributions. The ABC method can be applied using other reported summary statistics such as the posterior mean and 95 % credible interval when Bayesian analysis has been employed.
Full-text · Article · Apr 2015 · BMC Medical Research Methodology
[Show abstract][Hide abstract] ABSTRACT: Dosimetic uncertainties, particularly those that are shared among subgroups of a study population, can bias, distort or reduce the slope or significance of a dose response. Exposure estimates in studies of health risks from environmental radiation exposures are generally highly uncertain and thus, susceptible to these methodological limitations. An analysis was published in 2008 concerning radiation-related thyroid nodule prevalence in a study population of 2,994 villagers under the age of 21 years old between August 1949 and September 1962 and who lived downwind from the Semipalatinsk Nuclear Test Site in Kazakhstan. This dose-response analysis identified a statistically significant association between thyroid nodule prevalence and reconstructed doses of fallout-related internal and external radiation to the thyroid gland; however, the effects of dosimetric uncertainty were not evaluated since the doses were simple point "best estimates". In this work, we revised the 2008 study by a comprehensive treatment of dosimetric uncertainties. Our present analysis improves upon the previous study, specifically by accounting for shared and unshared uncertainties in dose estimation and risk analysis, and differs from the 2008 analysis in the following ways: 1. The study population size was reduced from 2,994 to 2,376 subjects, removing 618 persons with uncertain residence histories; 2. Simulation of multiple population dose sets (vectors) was performed using a two-dimensional Monte Carlo dose estimation method; and 3. A Bayesian model averaging approach was employed for evaluating the dose response, explicitly accounting for large and complex uncertainty in dose estimation. The results were compared against conventional regression techniques. The Bayesian approach utilizes 5,000 independent realizations of population dose vectors, each of which corresponds to a set of conditional individual median internal and external doses for the 2,376 subjects. These 5,000 population dose vectors reflect uncertainties in dosimetric parameters, partly shared and partly independent, among individual members of the study population. Risk estimates for thyroid nodules from internal irradiation were higher than those published in 2008, which results, to the best of our knowledge, from explicit accounting for dose uncertainty. In contrast to earlier findings, the use of Bayesian methods led to the conclusion that the biological effectiveness for internal and external dose was similar. Estimates of excess relative risk per unit dose (ERR/Gy) for males (177 thyroid nodule cases) were almost 30 times those for females (571 cases) and were similar to those reported for thyroid cancers related to childhood exposures to external and internal sources in other studies. For confirmed cases of papillary thyroid cancers (3 in males, 18 in females), the ERR/Gy was also comparable to risk estimates from other studies, but not significantly different from zero. These findings represent the first reported dose response for a radiation epidemiologic study considering all known sources of shared and unshared errors in dose estimation and using a Bayesian model averaging (BMA) method for analysis of the dose response.
Full-text · Article · Jan 2015 · Radiation Research
[Show abstract][Hide abstract] ABSTRACT: Simon, S. L., Preston, D. L., Linet, M. S., Miller, J. S., Sigurdson, A. J., Alexander, B. H., Kwon, D., Yoder, R. C., Bhatti, P., Little, M. P., Rajaraman, P., Melo, D., Drozdovitch, V., Weinstock, R. M. and Doody, M. M. Radiation Organ Doses Received in a Nationwide Cohort of U.S. Radiologic Technologists: Methods and Findings. Radiat. Res. 182, 507–528 (2014).
In this article, we describe recent methodological enhancements and findings from the dose reconstruction component of a study of health risks among U.S. radiologic technologists. An earlier version of the dosimetry published in 2006 used physical and statistical models, literature-reported exposure measurements for the years before 1960, and archival personnel monitoring badge data from cohort members through 1984. The data and models previously described were used to estimate annual occupational radiation doses for 90,000 radiological technologists, incorporating information about each individual’s employment practices based on a baseline survey conducted in the mid-1980s. The dosimetry methods presented here, while using many of the same methods as before, now estimate 2.23 million annual badge doses (personal dose equivalent) for the years 1916–1997 for 110,374 technologists, but with numerous methodological improvements. Every technologist’s annual dose is estimated as a probability density function to reflect uncertainty about the true dose. Multiple realizations of the entire cohort distribution were derived to account for shared uncertainties and possible biases in the input data and assumptions used. Major improvements in the dosimetry methods from the earlier version include: A substantial increase in the number of cohort member annual badge dose measurements; Additional information on individual apron usage obtained from surveys conducted in the mid-1990s and mid-2000s; Refined modeling to develop lognormal annual badge dose probability density functions using censored data regression models; Refinements of cohort-based annual badge probability density functions to reflect individual work patterns and practices reported on questionnaires and to more accurately assess minimum detection limits; and Extensive refinements in organ dose conversion coefficients to account for uncertainties in radiographic machine settings for the radiographic techniques employed. For organ dose estimation, we rely on well-researched assumptions about critical exposure-related variables and their changes over the decades, including the peak kilovoltage and filtration typically used in conducting radiographic examinations, and the usual body location for wearing radiation monitoring badges, the latter based on both literature and national recommendations. We have derived organ dose conversion coefficients based on air-kerma weighting of photon fluences from published X-ray spectra and derived energy-dependent transmission factors for protective lead aprons of different thicknesses. Findings are presented on estimated organ doses for 12 organs and tissues: red bone marrow, female breast, thyroid, brain, lung, heart, colon, ovary, testes, skin of trunk, skin of head and neck and arms, and lens of the eye.
Full-text · Article · Nov 2014 · Radiation Research
[Show abstract][Hide abstract] ABSTRACT: Most conventional risk analysis methods rely on a single best estimate of
exposure per person which does not allow for adjustment for exposure-related
uncertainty. Here, we propose a Bayesian model averaging method to properly
quantify the relationship between radiation dose and disease outcomes by
accounting for shared and unshared uncertainty in estimated dose. Our Bayesian
risk analysis method utilizes multiple realizations of sets (vectors) of doses
generated by a two-dimensional Monte Carlo simulation method that properly
separates shared and unshared errors in dose estimation. The exposure model
used in this work is taken from a study of the risk of thyroid nodules among a
cohort of 2,376 subjects following exposure to fallout resulting from nuclear
testing in Kazakhstan. We assessed the performance of our method through an
extensive series of simulation tests and comparisons against conventional
regression risk analysis methods. We conclude that when estimated doses contain
relatively small amounts of uncertainty, the Bayesian method using multiple
realizations of possibly true dose vectors gave similar results to the
conventional regression-based methods of dose-response analysis. However, when
large and complex mixtures of shared and unshared uncertainties are present,
the Bayesian method using multiple dose vectors had significantly lower
relative bias than conventional regression-based risk analysis methods as well
as a markedly increased capability to include the pre-established 'true' risk
coefficient within the credible interval of the Bayesian-based risk estimate.
An evaluation of the dose-response using our method is presented for an
epidemiological study of thyroid disease following radiation exposure.
Full-text · Article · Sep 2014 · Statistics in Medicine
[Show abstract][Hide abstract] ABSTRACT: Little, M.P., Kwon, D., Doi, K., Simon, S.L., Preston, D.L., Doody, M.M., Lee, T., Miller, J.S., Kampa, D.M., Bhatti, P., Tucker, J.D., Linet, M.S., Sigurdson, A.J., Association of Chromosome Translocation Rate with Low Dose Occupational Radiation Exposures in U.S. Radiologic Technologists. Radiat. Res. 182, 1-17 (2014).
Chromosome translocations are a well-recognized biological marker of radiation exposure and cancer risk. However, there is uncertainty about the lowest dose at which excess translocations can be detected, and whether there is temporal decay of induced translocations in radiation-exposed populations. Dosimetric uncertainties can substantially alter the shape of dose-response relationships; although regression-calibration methods have been used in some datasets, these have not been applied in radio-occupational studies, where there are also complex patterns of shared and unshared errors that these methods do not account for.
In this paper we evaluated the relationship between estimated occupational ionizing radiation doses and chromosome translocation rates using fluorescent in situ hybridization in 238 US radiologic technologists selected from a large cohort. Estimated cumulative red-bone-marrow doses (mean 29.3 mGy, range 0-135.7 mGy) were based on available badge-dose measurement data and on questionnaire-reported work-history factors. Dosimetric assessment uncertainties were evaluated using regression-calibration, Bayesian, and Monte-Carlo maximum-likelihood methods, taking account of shared and unshared error, and adjusted for overdispersion.
There was a significant dose response for estimated occupational radiation exposure, adjusted for questionnaire-based personal diagnostic radiation, age, sex, and study group (5.7 translocations per 100 whole-genome cell equivalents per Gy, 95% CI 0.2, 11.3, p=0.0440). A significant increasing trend with dose continued to be observed for individuals with estimated doses <100 mGy. For combined estimated occupational and personal diagnostic medical radiation exposures, there was a borderline-significant modifying effect of age (p=0.0704), but little evidence (p>0.5) of temporal decay of induced translocations. The three methods of analysis to adjust for dose uncertainty gave similar results.
In summary, chromosome translocation dose-response slopes were detectable down to <100 mGy, and were compatible with those observed in other radiation-exposed populations. However, there are substantial uncertainties in both occupational and other (personal diagnostic medical) doses that may be imperfectly taken into account in our analysis.
Full-text · Article · Jun 2014 · Radiation Research
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
To provide dosimetric data for an epidemiologic study on the risk of second primary esophageal cancer among breast cancer survivors, by reconstructing the radiation dose incidentally delivered to the esophagus of 414 women treated with radiation therapy for breast cancer during 1943-1996 in North America and Europe.
Methods and materials:
We abstracted the radiation therapy treatment parameters from each patient's radiation therapy record. Treatment fields included direct chest wall (37% of patients), medial and lateral tangentials (45%), supraclavicular (SCV, 64%), internal mammary (IM, 44%), SCV and IM together (16%), axillary (52%), and breast/chest wall boosts (7%). The beam types used were (60)Co (45% of fields), orthovoltage (33%), megavoltage photons (11%), and electrons (10%). The population median prescribed dose to the target volume ranged from 21 Gy to 40 Gy. We reconstructed the doses over the length of the esophagus using abstracted patient data, water phantom measurements, and a computational model of the human body.
Fields that treated the SCV and/or IM lymph nodes were used for 85% of the patients and delivered the highest doses within 3 regions of the esophagus: cervical (population median 38 Gy), upper thoracic (32 Gy), and middle thoracic (25 Gy). Other fields (direct chest wall, tangential, and axillary) contributed substantially lower doses (approximately 2 Gy). The cervical to middle thoracic esophagus received the highest dose because of its close proximity to the SCV and IM fields and less overlying tissue in that part of the chest. The location of the SCV field border relative to the midline was one of the most important determinants of the dose to the esophagus.
Breast cancer patients in this study received relatively high incidental radiation therapy doses to the esophagus when the SCV and/or IM lymph nodes were treated, whereas direct chest wall, tangentials, and axillary fields contributed lower doses.
No preview · Article · Apr 2013 · International journal of radiation oncology, biology, physics