Radiation effects on atherosclerosis in atomic bomb survivors: a cross-sectional study using structural equation modeling.

Past reports indicated that total-body irradiation at low to moderate doses could be responsible for cardiovascular disease risks, but the mechanism remains unclear. The purpose of this study was to investigate the association between radiation exposure and atherosclerosis, an underlying pathology of cardiovascular diseases, in the Japanese atomic bomb survivors. We performed a cross-sectional study measuring 14 clinical-physiological atherosclerosis indicators during clinical exams from 2010 to 2014 in 3274 participants of the Adult Health Study cohort. Multivariable analyses were performed by using a structural equation model with latent factors representing underlying atherosclerotic pathologies: (1) arterial stiffness, (2) calcification, and (3) plaque　as measured with indicators chosen a priori on the basis of clinical-physiological knowledge. Radiation was linearly associated with calcification (standardized coefficient per Gy 0.15, 95 % confidence interval: CI [0.070, 0.23]) and plaque (0.11, 95 % CI [0.029, 0.20]), small associations that were comparable to about 2 years of aging per Gy of radiation exposure, but not with arterial stiffness (0.036, 95 % CI [- 0.025, 0.095]). The model fitted better and had narrower confidence intervals than separate ordinary regression models explaining individual indicators independently. The associations were less evident when the dose range was restricted to a maximum of 2 or 1 Gy. By combining individual clinical-physiological indicators that are correlated because of common, underlying atherosclerotic pathologies, we found a small, but significant association of radiation with atherosclerosis.

Causal mediation analysis in nested case-control studies using conditional logistic regression.

The paper proposes an approach to causal mediation analysis in nested case-control study designs, often incorporated with countermatching schemes using conditional likelihood, and we compare the method's performance to that of mediation analysis using the Cox model for the full cohort with a continuous or dichotomous mediator. Simulation studies are conducted to assess our proposed method and investigate the efficiency relative to the cohort. We illustrate the method using actual data from two studies of potential mediation of radiation risk conducted within the Adult Health Study cohort of atomic-bomb survivors. The performance becomes comparable to that based on the full cohort, illustrating the potential for valid mediation analysis based on the reduced data obtained through the nested case-control design.

Radiation exposure and longitudinal changes in peripheral monocytes over 50 years: the Adult Health Study of atomic-bomb survivors.

Enhanced inflammatory responses have been suggested decades after radiation exposure in atomic-bomb survivors, but cellular and molecular alterations related to prolonged inflammation remain unclear. This study, utilizing longitudinal haematological data over 50 years for 14 000 persons, investigated whether radiation exposure promoted the relative increase in peripheral myeloid cells, known as an aging-associated indicator of low-grade inflammation. Statistical modelling was performed with a linear mixed-effects model for leucocyte subsets, together with a proportional hazards regression model for all-cause mortality. We found that age trends in lymphocyte, neutrophil and monocyte percentages or counts differed before versus after age 60 years. Radiation dose was associated with monocyte percentages and counts, but not with the lymphoid-myeloid cell ratio. Radiation effects on monocytes were stronger after versus before age 60 years. Increases in monocyte percentages and counts were associated with higher risk of all-cause mortality. Studies of chromosomal aberrations have shown a clonal expansion of haematopoietic stem cells among atomic-bomb survivors. Therefore, radiation exposure might accelerate aging-associated clonal haematopoiesis, which could result in a long-lasting elevation of circulating monocytes.

Low thyroid function is not associated with an accelerated deterioration in renal function.

BACKGROUND: Chronic kidney disease (CKD) is frequently accompanied by thyroid hormone dysfunction. It is currently unclear whether these alterations are the cause or consequence of CKD. This study aimed at studying the effect of thyroid hormone alterations on renal function in cross-sectional and longitudinal analyses in individuals from all adult age groups. METHODS: Individual participant data (IPD) from 16 independent cohorts having measured thyroid stimulating hormone, free thyroxine levels and creatinine levels were included. Thyroid hormone status was defined using clinical cut-off values. Estimated glomerular filtration rates (eGFR) were calculated by means of the four-variable Modification of Diet in Renal Disease (MDRD) formula. For this IPD meta-analysis, eGFR at baseline and eGFR change during follow-up were computed by fitting linear regression models and linear mixed models in each cohort separately. Effect estimates were pooled using random effects models. RESULTS: A total of 72 856 individuals from 16 different cohorts were included. At baseline, individuals with overt hypothyroidism (n = 704) and subclinical hypothyroidism (n = 3356) had a average (95% confidence interval) -4.07 (-6.37 to -1.78) and -2.40 (-3.78 to -1.02) mL/min/1.73 m2 lower eGFR as compared with euthyroid subjects (n = 66 542). In (subclinical) hyperthyroid subjects (n = 2254), average eGFR was 3.01 (1.50-4.52) mL/min/1.73 m2 higher. During 329 713 patient years of follow-up, eGFR did not decline more rapidly in individuals with low thyroid function compared with individuals with normal thyroid function. CONCLUSIONS: Low thyroid function is not associated with a deterioration of renal function. The cross-sectional association may be explained by renal dysfunction causing thyroid hormone alterations.

Choice reaction time and grip strength as predictors of cardiovascular mortality in middle-aged and elderly Japanese: from the Radiation Effects Research Foundation Adult Health study.

BACKGROUND: Cognitive function and physical function are important predictors of mortality. AIM: To investigate whether or not reaction time (RT) as a cognitive function and grip strength (GS) as a physical function were associated, alone or in combination, with mortality from heart disease or stroke. METHODS: The subjects included 4901 Adult Health Study participants in Hiroshima who had undergone RT and GS measurements, were 35-74 years old at baseline (1970-1972) and were followed until the end of 2007. RESULTS: After adjustment for other potential risk factors, RT was positively and GS was negatively associated with mortality from both heart disease and stroke. These associations were persistent in the model when adjusting simultaneously for RT, GS and other factors, but hazard ratios were attenuated. When we evaluated the associations by baseline age and gender, we found the greater hazard ratios for RT in the younger cohort, but no clear modification by age for GS. The interaction between RT and GS was statistically significant (P = 0.012) for stroke mortality. In the stratified analyses divided using the age-specific median value of RT or GS, the estimated hazard ratio of stroke mortality for RT was significant in participants with weak or strong GS but greater in the former, and for GS, it was only significant in participants with slow RT. CONCLUSION: RT and GS, alone and in combination, predicted heart disease and stroke mortalities. Interventions for both cognitive function and physical function may be beneficial for the prevention of cardiovascular disease mortality.

Prognostic Significance of Premature Ventricular Contractions without Obvious Heart Diseases Determined by Standard 12-Lead Electrocardiography Considering their Morphology.

BACKGROUND: Although ventricular premature contraction (VPC) commonly arises in subjects with and without heart diseases, the prognosis of VPC has remained controversial and the effect of their morphology on mortality has not been fully determined in subjects without obvious heart diseases. The objective of this study was to assess the morphologic effect of VPC on mortality. METHODS: Japanese atomic bomb survivors (n = 6685) underwent baseline health examinations and standard 12-lead electrocardiogram (ECG) between January 1990 and December 1991. Of these, we extracted data from 5,685 (67.1% women) subjects who had neither heart diseases nor electrocardiographic abnormalities at baseline. Among them, we identified 131 VPC cases using standard 12-lead ECG and classified them into left bundle branch block (LBBB) type (n = 74), right bundle branch block (RBBB) type (n = 21), and undetermined type (n = 36) according to their morphology. These subjects were followed up until December 2008; we compared all-cause, cardiac and coronary heart disease (CHD) mortality rates using multivariate Cox regression analysis between those with and without VPC. RESULTS: No VPCs were associated with all-cause and cardiac mortality, but the LBBB type was significantly associated with CHD mortality (hazard ratio, 2.73; 95% confidence interval, 1.11-6.73) after controlling for age, sex, smoking status, alcohol consumption, and underlying diseases. CONCLUSIONS: Among Japanese atomic bomb survivors without obvious heart diseases, LBBB-type VPC was associated with increased CHD mortality. Larger studies are needed to confirm the effect of morphology as it might help to predict the risk.

Associations of body mass index, smoking, and alcohol consumption with prostate cancer mortality in the Asia Cohort Consortium.

Many potentially modifiable risk factors for prostate cancer are also associated with prostate cancer screening, which may induce a bias in epidemiologic studies. We investigated the associations of body mass index (weight (kg)/height (m)(2)), smoking, and alcohol consumption with risk of fatal prostate cancer in Asian countries where prostate cancer screening is not widely utilized. Analysis included 18 prospective cohort studies conducted during 1963-2006 across 6 countries in southern and eastern Asia that are part of the Asia Cohort Consortium. Body mass index, smoking, and alcohol intake were determined by questionnaire at baseline, and cause of death was ascertained through death certificates. Analysis included 522,736 men aged 54 years, on average, at baseline. During 4.8 million person-years of follow-up, there were 634 prostate cancer deaths (367 prostate cancer deaths across the 11 cohorts with alcohol data). In Cox proportional hazards analyses of all cohorts in the Asia Cohort Consortium, prostate cancer mortality was not significantly associated with obesity (body mass index >25: hazard ratio (HR) = 1.08, 95% confidence interval (CI): 0.85, 1.36), ever smoking (HR = 1.00, 95% CI: 0.84, 1.21), or heavy alcohol intake (HR = 1.00, 95% CI: 0.74, 1.35). Differences in prostate cancer screening and detection probably contribute to differences in the association of obesity, smoking, or alcohol intake with prostate cancer risk and mortality between Asian and Western populations and thus require further investigation.

Serum interleukin-6 associated with hepatocellular carcinoma risk: a nested case-control study.

Inflammatory markers have been associated with increased risk of several cancers, including colon, lung, breast and liver, but the evidence is inconsistent. We conducted a nested case-control study in the longitudinal cohort of atomic-bomb survivors. The study included 224 hepatocellular carcinoma (HCC) cases and 644 controls individually matched to cases on gender, age, city and time and method of serum storage, and countermatched on radiation dose. We measured C-reactive protein (CRP) and interleukin (IL)-6 using stored sera obtained within 6 years before HCC diagnosis from 188 HCC cases and 605 controls with adequate volumes of donated blood. Analyses with adjustment for hepatitis virus infection, alcohol consumption, smoking habit, body mass index (BMI) and radiation dose showed that relative risk (RR) of HCC [95% confidence interval (CI)] in the highest tertile of CRP levels was 1.94 (0.72-5.51) compared to the lowest tertile (p = 0.20). RR of HCC (95% CI) in the highest tertile of IL-6 levels was 5.12 (1.54-20.1) compared to the lowest tertile (p = 0.007). Among subjects with BMI > 25.0 kg/m(2) , a stronger association was found between a 1-standard deviation (SD) increase in log IL-6 and HCC risk compared to subjects in the middle quintile of BMI (21.3-22.9 kg/m(2) ), resulting in adjusted RR (95% CI) of 3.09 (1.78-5.81; p = 0.015). The results indicate that higher serum levels of IL-6 are associated with increased HCC risk, independently of hepatitis virus infection, lifestyle-related factors and radiation exposure. The association is especially pronounced among subjects with obesity.

Burden of total and cause-specific mortality related to tobacco smoking among adults aged ≥ 45 years in Asia: a pooled analysis of 21 cohorts.

BACKGROUND: Tobacco smoking is a major risk factor for many diseases. We sought to quantify the burden of tobacco-smoking-related deaths in Asia, in parts of which men's smoking prevalence is among the world's highest. METHODS AND FINDINGS: We performed pooled analyses of data from 1,049,929 participants in 21 cohorts in Asia to quantify the risks of total and cause-specific mortality associated with tobacco smoking using adjusted hazard ratios and their 95% confidence intervals. We then estimated smoking-related deaths among adults aged ≥45 y in 2004 in Bangladesh, India, mainland China, Japan, Republic of Korea, Singapore, and Taiwan-accounting for ∼71% of Asia's total population. An approximately 1.44-fold (95% CI = 1.37-1.51) and 1.48-fold (1.38-1.58) elevated risk of death from any cause was found in male and female ever-smokers, respectively. In 2004, active tobacco smoking accounted for approximately 15.8% (95% CI = 14.3%-17.2%) and 3.3% (2.6%-4.0%) of deaths, respectively, in men and women aged ≥45 y in the seven countries/regions combined, with a total number of estimated deaths of ∼1,575,500 (95% CI = 1,398,000-1,744,700). Among men, approximately 11.4%, 30.5%, and 19.8% of deaths due to cardiovascular diseases, cancer, and respiratory diseases, respectively, were attributable to tobacco smoking. Corresponding proportions for East Asian women were 3.7%, 4.6%, and 1.7%, respectively. The strongest association with tobacco smoking was found for lung cancer: a 3- to 4-fold elevated risk, accounting for 60.5% and 16.7% of lung cancer deaths, respectively, in Asian men and East Asian women aged ≥45 y. CONCLUSIONS: Tobacco smoking is associated with a substantially elevated risk of mortality, accounting for approximately 2 million deaths in adults aged ≥45 y throughout Asia in 2004. It is likely that smoking-related deaths in Asia will continue to rise over the next few decades if no effective smoking control programs are implemented. Please see later in the article for the Editors' Summary.

Naive CD4 T Cells Highly Expressing the Inflammatory Chemokine Receptor CXCR3 Increase with Age and Radiation Exposure in Atomic Bomb Survivors.

The numbers of naive T cells that react to novel pathogens not yet encountered by an immune system, decrease during aging, mainly due to age-associated involution of the thymus. CD45RA+ naive CD4 T cells consist of heterogeneous populations, including highly CXCR3-expressing cells that appear during the homeostatic proliferation of naive T cells and exhibit enhanced type-1 inflammatory phenotypes. Based on previous evidence of radiation-associated reductions in thymic function and peripheral blood naive CD4 T cells, we hypothesized that the homeostatic proliferation of naive CD4 T cells compensates for deficits in peripheral T-cell populations after radiation injury, which may increase the proportion of CXCR3high cells in naive CD4 T cells and enhance inflammation. The statistical models employed in this study revealed positive associations between the number of CXCR3high naive CD4 T cells and age as well as radiation dose among 580 Hiroshima atomic bomb survivors. In addition, the CXCR3high cells in these survivors increased not only with the levels of homeostatic cytokines, IL6 and IL7, but also with those of inflammatory indicators, CXCL10 and CRP. These results suggest that thymic T-cell production deficiency due to radiation and aging results in enhanced homeostatic proliferation that drives the appearance of CXCR3high naive CD4 T cells poised for an inflammatory response. Molecular mechanisms and clinical relevance of increasing CXCR3high cells in naive CD4 T populations should be further investigated in the context of inflammatory disease development long after radiation exposure.

Reliability, stability during long-term storage, and intra-individual variation of circulating levels of osteopontin, osteoprotegerin, vascular endothelial growth factor-A, and interleukin-17A.

BACKGROUND: Studies in many populations have reported associations between circulating cytokine levels and various physiological or pathological conditions. However, the reliability of cytokine measurements in population studies, which measure cytokines in multiple assays over a prolonged period, has not been adequately examined; nor has stability during sample storage or intra-individual variation been assessed. METHODS: We assessed (1) analytical reliability in short- and long-term repeated measurements; (2) stability and analytical reliability during long-term sample storage, and (3) variability within individuals over seasons, of four cytokines-osteopontin (OPN), osteoprotegerin (OPG), vascular endothelial growth factor-A (VEGF-A), and interleukin-17A (IL-17A). Measurements in plasma or serum samples were made with commercial kits according to standard procedures. Estimation was performed by fitting a random or mixed effects linear model on the log scale. RESULTS: In repeated assays over a short period, OPN, OPG, and VEGF-A had acceptable reliability, with intra- and inter-assay coefficients of variation (CV) less than 0.11. Reliability of IL-17A was poor, with inter- and intra-assay CV 0.85 and 0.43, respectively. During long-term storage, OPG significantly decayed (- 33% per year; 95% confidence interval [- 54, - 3.7]), but not OPN or VEGF-A (- 0.3% or - 6.3% per year, respectively). Intra- and inter-assay CV over a long period were comparable to that in a short period except for a slight increase in inter-assay CV of VEGF-A. Within-individual variation was small for OPN and VEGF-A, with intra-class correlations (ICC) 0.68 and 0.83, respectively, but large for OPG (ICC 0.11). CONCLUSIONS: We conclude that OPN and VEGF-A can be reliably measured in a large population, that IL-17A is suitable only for small experiments, and that OPG should be assessed with caution due to degradation during storage and intra-individual variation. The overall results of our study illustrate the need for validation under relevant conditions when measuring circulating cytokines in population studies.

Circulating microRNA-22 correlates with microRNA-122 and represents viral replication and liver injury in patients with chronic hepatitis B.

Hepatitis B virus (HBV) infection is associated with increased expression of microRNA-122. Serum microRNA-122 and microRNA-22 levels were analyzed in 198 patients with chronic HBV who underwent liver biopsy and were compared with quantitative measurements of HBsAg, HBeAg, HBV DNA, and other clinical and histological findings. Levels of serum microRNA-122 and microRNA-22 were determined by reverse transcription-TaqMan PCR. Serum levels of microRNA-122 and microRNA-22 were correlated (R(2) = 0.576; P < 0.001), and both were elevated in chronic HBV patients. Significant linear correlations were found between microRNA-122 or microRNA-22 and HBsAg levels (R(2) = 0.824, P < 0.001 and R(2) = 0.394, P < 0.001, respectively) and ALT levels (R(2) = 0.498, P < 0.001 and R(2) = 0.528, P < 0.001, respectively). MicroRNA-122 levels were also correlated with HBV DNA titers (R(2) = 0.694, P < 0.001 and R(2) = 0.421, P < 0.001). Levels of these microRNAs were significantly higher in HBeAg-positive patients compared to HBeAg-negative patients (P < 0.001 and P < 0.001). MicroRNA-122 levels were also lower in patients with advanced liver fibrosis (P < 0.001) and lower inflammatory activity (P < 0.025). These results suggest that serum micro-RNA levels are significantly associated with multiple aspects of HBV infection. The biological meaning of the correlation between microRNA-122 and HBsAg and should be investigated further.

Radiation risk of individual multifactorial diseases in offspring of the atomic-bomb survivors: a clinical health study.

There is no convincing evidence regarding radiation-induced heritable risks of adult-onset multifactorial diseases in humans, although it is important from the standpoint of protection and management of populations exposed to radiation. The objective of the present study was to examine whether parental exposure to atomic-bomb (A-bomb) radiation led to an increased risk of common polygenic, multifactorial diseases-hypertension, hypercholesterolaemia, diabetes mellitus, angina pectoris, myocardial infarction or stroke-in the first-generation (F1) offspring of A-bomb survivors. A total of 11,951 F1 offspring of survivors in Hiroshima or Nagasaki, conceived after the bombing, underwent health examinations to assess disease prevalence. We found no evidence that paternal or maternal A-bomb radiation dose, or the sum of their doses, was associated with an increased risk of any multifactorial diseases in either male or female offspring. None of the 18 radiation dose-response slopes, adjusted for other risk factors for the diseases, was statistically significantly elevated. However, the study population is still in mid-life (mean age 48.6 years), and will express much of its multifactorial disease incidence in the future, so ongoing longitudinal follow-up will provide increasingly informative risk estimates regarding hereditary genetic effects for incidence of adult-onset multifactorial disease.

A report from the 2013 international workshop: radiation and cardiovascular disease, Hiroshima, Japan.

Two longitudinal cohort studies of Japanese atomic bomb survivors-the life span study (LSS) and the adult health study (AHS)-from the Radiation Effects Research Foundation (RERF) indicate that total body irradiation doses less than 1 Gy are associated with an increased risk of cardiovascular disease (CVD), but several questions about this association remain.In particular, the diversity of heart disease subtypes and the high prevalence of other risk factors complicate the estimates of radiation effects. Subtype-specific analyses with more reliable diagnostic criteria and measurement techniques are needed. The radiation effects on CVD risk are probably tissue-reaction (deterministic) effects, so the dose-response relationships for various subtypes of CVD may be nonlinear and therefore should be explored with several types of statistical models.Subpopulations at high risk need to be identified because effects at lower radiation doses may occur primarily in these susceptible subpopulations. Whether other CVD risk factors modify radiation effects also needs to be determined. Finally, background rates for various subtypes of CVD have historically differed substantially between Japanese and Western populations, so the generalisability to other populations needs to be examined.Cardiovascular disease mechanisms and manifestations may differ between high-dose local irradiation and low-dose total body irradiation (TBI)-microvascular damage and altered metabolism from low-dose TBI, but coronary artery atherosclerosis and thrombotic myocardial infarcts at high localised doses. For TBI, doses to organs other than the heart may be important in pathogenesis of CVD, so data on renal and liver disorders, plaque instability, microvascular damage, metabolic disorders, hypertension and various CVD biomarkers and risk factors are needed. Epidemiological, clinical and experimental studies at doses of less than 1 Gy are necessary to clarify the effects of radiation on CVD risk.

Early-life atomic-bomb irradiation accelerates immunological aging and elevates immune-related intracellular reactive oxygen species.

Reactive oxygen species (ROS) play an important role in immune responses; however, their excessive production and accumulation increases the risk of inflammation-related diseases. Although irradiation is known to accelerate immunological aging, the underlying mechanism is still unclear. To determine the possible involvement of ROS in this mechanism, we examined 10,023 samples obtained from 3752 atomic-bomb survivors in Hiroshima and Nagasaki, who participated in repeated biennial examinations from 2008 to 2016, for the effects of aging and radiation exposure on intracellular ROS (H2 O2 and O2 •- ) levels, percentages of T-cell subsets, and the effects of radiation exposure on the relationship between cell percentages and intracellular ROS levels in T-cell subsets. The cell percentages and intracellular ROS levels in T-cell subsets were measured using flow cytometry, with both fluorescently labeled antibodies and the fluorescent reagents, carboxy-DCFDA and hydroethidine. The percentages of naïve CD4+ and CD8+ T cells decreased with increasing age and radiation dose, while the intracellular O2 •- levels in central and effector memory CD8+ T cells increased. Additionally, when divided into three groups based on the percentages of naïve CD4+ T cells, intracellular O2 •- levels of central and effector memory CD8+ T cells were significantly elevated with the lowest radiation dose group in the naïve CD4+ T cells. Thus, the radiation exposure-induced decrease in the naïve CD4+ T cell pool size may reflect decreased immune function, resulting in increased intracellular ROS levels in central and effector memory CD8+ T cells, and increased intracellular oxidative stress.

Lenvatinib activates anti-tumor immunity by suppressing immunoinhibitory infiltrates in the tumor microenvironment of advanced hepatocellular carcinoma.

BACKGROUND: Lenvatinib, a multiple receptor tyrosine kinase inhibitor, might exert antitumor effects via tumor immune modulation. However, changes in the tumor immune microenvironment induced by lenvatinib are poorly understood. We investigated the effect of lenvatinib on immune features in clinical samples from patients with hepatocellular carcinoma. METHODS: Fifty-one patients with advanced hepatocellular carcinoma who received lenvatinib monotherapy as first-line treatment were enrolled. We collected blood sample (n = 51) and tumor tissue (n, baseline/four weeks after treatment initiation/post-progression = 50/8/12). DNA, RNA, and proteins extracted from the tissues were subjected to multi-omics analysis, and patients were classified into two groups according to baseline immune status. Each group was investigated in terms of the dynamics of tumor signaling. We also longitudinally analyzed circulating immune proteins and chemokines in peripheral blood. RESULTS: Here we show that lenvatinib has similar anti-tumor efficacy with objective response rate and progression-free survival in both Immune-Hot and Immune-Cold subtypes. Immune signatures associated with T-cell functions and interferon responses are enriched in the early phase of treatment, while signatures associated with immunoinhibitory cells are downregulated along with efficient vascular endothelial growth factor receptor and fibroblast growth factor receptor blockades. These findings are supported by imaging mass cytometry, T-cell receptor repertoire analysis and kinetics of circulating proteins. We also identify interleukin-8 and angiopoietin-2 as possible targets of intervention to overcome resistance to existing immunotherapies. CONCLUSIONS: Our findings show the ability of lenvatinib to modulate tumor immunity in clinical samples of hepatocellular carcinoma.

Two types of therapy for liver cancer are immunotherapy and anti-angiogenic therapy. Immunotherapy helps the patient's immune system to attack the tumor. Anti-angiogenic therapy blocks the formation of new blood vessels (angiogenesis) in the tumor, and this type of therapy might also impact the immune system. We analyzed changes in the immune characteristics of human liver cancer samples induced by lenvatinib, an anti-angiogenic therapy. Patient outcomes on lenvatinib did not depend on the immune features of the tumor before treatment. However, immune characteristics of the tumors did change after treatment, and this may mean these tumors become easier to treat with immunotherapies. These findings help us to understand the effects of lenvatinib in liver cancer and whether, for example, it might be useful to combine this drug with immunotherapy.

Impact of radiation and hepatitis virus infection on risk of hepatocellular carcinoma.

UNLABELLED: In cohort studies of atomic bomb survivors and Mayak nuclear facility workers, radiation-associated increases in liver cancer risk were observed, but hepatitis B virus (HBV) and hepatitis C virus (HCV) infections were not taken strictly into account. We identified 359 hepatocellular carcinoma (HCC) cases between 1970 and 2002 in the cohort of atomic bomb survivors and estimated cumulative incidence of HCC by radiation dose. To investigate contributions of radiation exposure and hepatitis virus infection to HCC risk, we conducted a nested case-control study using sera stored before HCC diagnosis in the longitudinal cohort of atomic bomb survivors. The study included 224 HCC cases and 644 controls that were matched to the cases on gender, age, city, and time and method of serum storage, and countermatched on radiation dose. The cumulative incidence of HCC by follow-up time and age increased significantly with radiation dose. The relative risk (RR) of HCC for radiation at 1 Gy was 1.67 (95% confidence interval: 1.22-2.35) with adjustment for alcohol consumption, body mass index (BMI), and smoking habit, whereas the RRs for HBV or HCV infection alone were 63 (20-241) and 83 (36-231) with such adjustment, respectively. Those estimates changed little when radiation and hepatitis virus infection were fit simultaneously. The RR of non-B, non-C HCC at 1 Gy was 1.90 (1.02-3.92) without adjustment for alcohol consumption, BMI, or smoking habit and 2.74 (1.26-7.04) with such adjustment. CONCLUSION: These results indicate that radiation exposure and HBV and HCV infection are associated independently with increased HCC risk. In particular, radiation exposure was a significant risk factor for non-B, non-C HCC with no apparent confounding by alcohol consumption, BMI, or smoking habit.

Proportional hazards regression in epidemiologic follow-up studies: an intuitive consideration of primary time scale.

In epidemiologic cohort studies of chronic diseases, such as heart disease or cancer, confounding by age can bias the estimated effects of risk factors under study. With Cox proportional-hazards regression modeling in such studies, it would generally be recommended that chronological age be handled nonparametrically as the primary time scale. However, studies involving baseline measurements of biomarkers or other factors frequently use follow-up time since measurement as the primary time scale, with no explicit justification. The effects of age are adjusted for by modeling age at entry as a parametric covariate. Parametric adjustment raises the question of model adequacy, in that it assumes a known functional relationship between age and disease, whereas using age as the primary time scale does not. We illustrate this graphically and show intuitively why the parametric approach to age adjustment using follow-up time as the primary time scale provides a poor approximation to age-specific incidence. Adequate parametric adjustment for age could require extensive modeling, which is wasteful, given the simplicity of using age as the primary time scale. Furthermore, the underlying hazard with follow-up time based on arbitrary timing of study initiation may have no inherent meaning in terms of risk. Given the potential for biased risk estimates, age should be considered as the preferred time scale for proportional-hazards regression with epidemiologic follow-up data when confounding by age is a concern.

Incidence of Diabetes in the Atomic Bomb Survivors: 1969-2015.

CONTEXT: Recent epidemiological studies have shown increased risk of diabetes among childhood cancer survivors who received high therapeutic doses of radiation, particularly to the total body or to the abdomen. However, the effect of low-to-moderate dose radiation (<4 Gy) on the risk of diabetes is still unknown. OBJECTIVES: To investigate the radiation effect on diabetes incidence among atomic bomb (A-bomb) survivors, and whether the dose response is modified by other factors including city, sex, and age at time of bombing (ATB). METHODS: 9131 participants without diabetes at baseline were observed through biennial clinical exams from 1969 to 2015. A Cox proportional hazards model was used to estimate hazard ratios (HR) to evaluate the dose response for diabetes incidence. RESULTS: During the study period, 1417 incident diabetes cases were identified. The overall crude incidence rate was 7.01/103 person-years. Radiation dose was significantly associated with diabetes incidence, with effect modification by city and age ATB. In Hiroshima, at ages 10 and 30 ATB, the HRs at 1 Gy of pancreatic radiation dose were 1.47 (95% CI, 1.31-1.66) and 1.13 (95% CI, 0.97-1.31), respectively. However, no significant radiation dose response was observed at these ages in Nagasaki. The HR for radiation dose was higher among those who were younger ATB and decreased 1% for each additional year of age. CONCLUSIONS: Among A-bomb survivors, a radiation association was suggested for incidence of diabetes. Results were inconsistent by city and age ATB, which could indicate potential confounding of the radiation association with diabetes.

Incorporating Baseline Outcome Data in Individual Participant Data Meta-Analysis of Non-randomized Studies.

Background: In non-randomized studies (NRSs) where a continuous outcome variable (e.g., depressive symptoms) is assessed at baseline and follow-up, it is common to observe imbalance of the baseline values between the treatment/exposure group and control group. This may bias the study and consequently a meta-analysis (MA) estimate. These estimates may differ across statistical methods used to deal with this issue. Analysis of individual participant data (IPD) allows standardization of methods across studies. We aimed to identify methods used in published IPD-MAs of NRSs for continuous outcomes, and to compare different methods to account for baseline values of outcome variables in IPD-MA of NRSs using two empirical examples from the Thyroid Studies Collaboration (TSC). Methods: For the first aim we systematically searched in MEDLINE, EMBASE, and Cochrane from inception to February 2021 to identify published IPD-MAs of NRSs that adjusted for baseline outcome measures in the analysis of continuous outcomes. For the second aim, we applied analysis of covariance (ANCOVA), change score, propensity score and the naïve approach (ignores the baseline outcome data) in IPD-MA from NRSs on the association between subclinical hyperthyroidism and depressive symptoms and renal function. We estimated the study and meta-analytic mean difference (MD) and relative standard error (SE). We used both fixed- and random-effects MA. Results: Ten of 18 (56%) of the included studies used the change score method, seven (39%) studies used ANCOVA and one the propensity score (5%). The study estimates were similar across the methods in studies in which groups were balanced at baseline with regard to outcome variables but differed in studies with baseline imbalance. In our empirical examples, ANCOVA and change score showed study results on the same direction, not the propensity score. In our applications, ANCOVA provided more precise estimates, both at study and meta-analytical level, in comparison to other methods. Heterogeneity was higher when change score was used as outcome, moderate for ANCOVA and null with the propensity score. Conclusion: ANCOVA provided the most precise estimates at both study and meta-analytic level and thus seems preferable in the meta-analysis of IPD from non-randomized studies. For the studies that were well-balanced between groups, change score, and ANCOVA performed similarly.