Meta-analysis of Rare Diseases in Occupational Epidemiology.

At the outset of this research in the early 2000s, the application of meta-analysis in observational epidemiology, including occupational epidemiology was regarded as controversial because of the greater potential for bias in such studies compared with randomized controlled clinical trials. This remains true even in 2017. The overall aim for this research is to identify the best approaches to the use of meta-analysis in the occupational health setting, and to summarise through meta-analysis the evidence at to whether or not occupational exposure to formaldehyde is an occupational carcinogen. Chapter 2 of this thesis concluded that meta-analysis in occupational epidemiology was becoming increasingly popular, but that its limitations appear not to have been heeded in practice. Two principal issues were identified: the heterogeneity of exposures estimates and the pooling of standardized mortality ratios from different study populations with different characteristics including length of follow-up. By 2016, neither of these issues had been addressed in the literature. Chapter 3 contains a description of the published statistical methods available for meta-analysis up to 2001. Methodological developments continue within the discipline of randomized controlled clinical trials and recently include the advent of multivariate methods and network analysis. It has been recommended that any new methods should be backed up by simulations. Chapter 4 concludes that the default approach adopted by most statistical packages could not deal with such studies and excluded them from any calculations. In meta-analyses of rare diseases, this biases the meta-relative risks upwards. Approaches that avoided exclusion of such studies are considered, in particular analyses on the original untransformed scale rather than the log scale. Chapter 5 concludes that there remains insufficient evidence for an association. There was significant heterogeneity in the lung cancer results and so this is a random effects analysis; the analyses for nasopharyngeal and sinonasal cancer contains no such heterogeneity and so are fixed effect analyses. The final chapter concludes that, when studies with zero cases are not excluded, there is insufficient evidence of an increased risk of lung cancer, nasopharyngeal cancer or sinonasal cancer, and that further methodological developments are still required to deal with the pooling of occupational epidemiological studies in relation to study characteristics, exposure assessments and standardised mortality ratios

Mortality among US employees of a large computer manufacturing company: 1969–2001

BACKGROUND: Previous studies suggested increased cancer incidence and mortality in workers exposed to solvents and other chemicals in computer manufacturing jobs. Most previous studies were of small cohorts and findings were inconsistent. A lawsuit involving a large U.S. company produced a data file for analysis. This study sought to elucidate patterns of mortality in workers who were engaged manufacturing computers and related electronic components in the largest database available to date. METHODS: A proportional mortality and proportional cancer mortality analysis of deaths in eligible workers between 1969 and 2001 was carried out, with U.S. population mortality data as the standard for comparison. Mortality and work history data was from corporate mortality and work history files produced during litigation and standard U.S. and state mortality files. The study base comprised 31,941 decedents who died between 1969 and 2001, who had worked for at least five years and whose death information was collected in the corporate mortality file. Proportional mortality ratios (PMRs) and Proportional Cancer Mortality Ratios (PCMRs) and their 95% confidence intervals were computed for 66 causes of death in males and females. RESULTS: PMRs for all cancers combined were elevated in males (PMR = 107; 95% CI = 105–109) and females (PMR = 115; 95% CI = 110–119); several specific cancers and other causes of death were also significantly elevated in both males and females. There were reduced deaths due to non-malignant respiratory disease in males and females and heart disease in females; several specific cancers and other causes of death were significantly reduced in both males and females. Proportional cancer mortality ratios (PCMRs) for brain and central nervous system cancer were elevated (PCMR = 166; 95% CI = 129–213), kidney cancer (PCMR = 162; 95% CI = 124–212), melanoma of skin (PCMR = 179; 95% CI = 131–244) and pancreatic cancer (PCMR = 126; 95% CI = 101–157) were significantly elevated in male manufacturing workers. Kidney cancer (PCMR = 212; 95% CI = 116–387) and cancer of all lymphatic and hematopoietic tissue (PCMR = 162; 95% CI = 121–218) were significantly elevated in female manufacturing workers. CONCLUSION: Mortality was elevated due to specific cancers and among workers more likely to be exposed to solvents and other chemical exposures in manufacturing operations. Due to lack of individual exposure information, no conclusions are made about associations with any particular agent

A reference relative time-scale as an alternative to chronological age for cohorts with long follow-up

Background: Epidemiologists have debated the appropriate time-scale for cohort survival studies; chronological age or time-on-study being two such time-scales. Importantly, assessment of risk factors may depend on the choice of time-scale. Recently, chronological or attained age has gained support but a case can be made for a ‘reference relative time-scale’ as an alternative which circumvents difficulties that arise with this and other scales. The reference relative time of an individual participant is the integral of a reference population hazard function between time of entry and time of exit of the individual. The objective here is to describe the reference relative time-scale, illustrate its use, make comparison with attained age by simulation and explain its relationship to modern and traditional epidemiologic methods. Results: A comparison was made between two models; a stratified Cox model with age as the time-scale versus an un-stratified Cox model using the reference relative time-scale. The illustrative comparison used a UK cohort of cotton workers, with differing ages at entry to the study, with accrual over a time period and with long follow-up. Additionally, exponential and Weibull models were fitted since the reference relative time-scale analysis need not be restricted to the Cox model. A simulation study showed that analysis using the reference relative time-scale and analysis using chronological age had very similar power to detect a significant risk factor and both were equally unbiased. Further, the analysis using the reference relative time-scale supported fully-parametric survival modelling and allowed percentile predictions and mortality curves to be constructed. Conclusions: The reference relative time-scale was a viable alternative to chronological age, led to simplification of the modelling process and possessed the defined features of a good time-scale as defined in reliability theory. The reference relative time-scale has several interpretations and provides a unifying concept that links contemporary approaches in survival and reliability analysis to the traditional epidemiologic methods of Poisson regression and standardised mortality ratios. The community of practitioners has not previously made this connection

Factors affecting the mesothelioma detection rate within national and international epidemiological studies: insights from Scottish linked cancer registry-mortality data

ICD-9 code 163 (malignant neoplasm of pleura) listed as underlying cause of death detected only 40% of Scottish mesothelioma cases (all body sites) from the cancer registry in 1981–1999. This is lower than both the previously published 55% figure, derived from UK mesothelioma register data 1986–1991, which is based on any mention of mesothelioma on death certificates, cross-referenced to cancer registry data, and the 44% figure derived from Scottish mortality data 1981–1999, which captured any mention of mesothelioma on the death certificate. Detection from cancer registry data increased to 75% under ICD-10 in Scotland, confirming earlier predictions of the benefit of ICD-10's more specific mesothelioma codes. Including the accidental poisoning codes E866.4 (ICD-9) and X49 (ICD-10), covering poisoning by ‘unspecified' and ‘other' causes, which appear to have been used as coding surrogates for mesothelioma when asbestos exposure was explicitly mentioned in deaths suggestive of a mesothelioma, and which are recorded as the underlying cause of death in 4–7% of mesotheliomas, may improve the mesothelioma detection rate in future epidemiological studies

Light smoking at base-line predicts a higher mortality risk to women than to men; evidence from a cohort with long follow-up

BACKGROUND: There is conflicting evidence as to whether smoking is more harmful to women than to men. The UK Cotton Workers’ Cohort was recruited in the 1960s and contained a high proportion of men and women smokers who were well matched in terms of age, job and length of time in job. The cohort has been followed up for 42 years. METHODS: Mortality in the cohort was analysed using an individual relative survival method and Cox regression. Whether smoking, ascertained at baseline in the 1960s, was more hazardous to women than to men was examined by estimating the relative risk ratio women to men, smokers to never smoked, for light (1–14), medium (15–24), heavy (25+ cigarettes per day) and former smoking. RESULTS: For all-cause mortality relative risk ratios were 1.35 for light smoking at baseline (95% CI 1.07-1.70), 1.15 for medium smoking (95% CI 0.89-1.49) and 1.00 for heavy smoking (95% CI 0.63-1.61). Relative risk ratios for light smoking at baseline for circulatory system disease was 1.42 (95% CI 1.01 to 1.98) and for respiratory disease was 1.89 (95% CI 0.99 to 3.63). Heights of participants provided no explanation for the gender difference. CONCLUSIONS: Light smoking at baseline was shown to be significantly more hazardous to women than to men but the effect decreased as consumption increased indicating a dose response relationship. Heavy smoking was equally hazardous to both genders. This result may help explain the conflicting evidence seen elsewhere. However gender differences in smoking cessation may provide an alternative explanation

Concussion and long-term cognitive function among rugby players-The BRAIN Study

OBJECTIVE: The BRAIN Study was established to assess the associations between self-reported concussions and cognitive function among retired rugby players. METHODS: Former elite-level male rugby union players (50+ years) in England were recruited. Exposure to rugby-related concussion was collected using the BRAIN-Q tool. The primary outcome measure was the Preclinical Alzheimer Cognitive Composite (PACC). Linear regressions were conducted for the association between concussion and PACC score, adjusting for confounders. RESULTS: A total of 146 participants were recruited. The mean (standard deviation) length of playing career was 15.8 (5.4) years. A total of 79.5% reported rugby-related concussion(s). No association was found between concussion and PACC (β -0.03 [95% confidence interval (CI): -1.31, 0.26]). However, participants aged 80+ years reporting 3+ concussions had worse cognitive function than those without concussion (β -1.04 [95% CI: -1.62, -0.47]). CONCLUSIONS: Overall there was no association between concussion and cognitive function; however, a significant interaction with age revealed an association in older participants

Occupational, domestic and environmental mesothelioma risks in the British population: a case–control study

We obtained lifetime occupational and residential histories by telephone interview with 622 mesothelioma patients (512 men, 110 women) and 1420 population controls. Odds ratios (ORs) were converted to lifetime risk (LR) estimates for Britons born in the 1940s. Male ORs (95% confidence interval (CI)) relative to low-risk occupations for >10 years of exposure before the age of 30 years were 50.0 (25.8–96.8) for carpenters (LR 1 in 17), 17.1 (10.3–28.3) for plumbers, electricians and painters, 7.0 (3.2–15.2) for other construction workers, 15.3 (9.0–26.2) for other recognised high-risk occupations and 5.2 (3.1–8.5) in other industries where asbestos may be encountered. The LR was similar in apparently unexposed men and women (∼1 in 1000), and this was approximately doubled in exposed workers' relatives (OR 2.0, 95% CI 1.3–3.2). No other environmental hazards were identified. In all, 14% of male and 62% of female cases were not attributable to occupational or domestic asbestos exposure. Approximately half of the male cases were construction workers, and only four had worked for more than 5 years in asbestos product manufacture

Possible pro-carcinogenic association of endotoxin on lung cancer among Shanghai women textile workers

Background: Endotoxin (lipopolysaccharide) is a widespread contaminant in many environmental settings. Since the 1970s, there has been generally consistent evidence indicating reduced risks for lung cancer associated with occupational endotoxin exposure. Methods: We updated a case–cohort study nested within a cohort of 267 400 female textile workers in Shanghai, China. We compared exposure histories of 1456 incident lung cancers cases diagnosed during 1989–2006 with those of a reference subcohort of 3022 workers who were free of lung cancer at the end of follow-up. We applied Cox proportional hazards modelling to estimate exposure–response trends, adjusted for age and smoking, for cumulative exposures lagged by 0, 10, and 20 years, and separately for time windows of ⩽15 and \u3e15 years since first exposure. Results: We observed no associations between cumulative exposure and lung cancer, irrespective of lag interval. In contrast, analyses by exposure time windows revealed modestly elevated, but not statistically significant relative risks (∼1.27) at the highest three exposure quintiles for exposures that occurred \u3e15 years since first exposure. Conclusions: The findings do not support a protective effect of endotoxin, but are suggestive of possible lung cancer promotion with increasing time since first exposure

Mesothelioma incidence surveillance systems and claims for workers’ compensation. Epidemiological evidence and prospects for an integrated framework

<p>Abstract</p> <p>Background</p> <p>Malignant mesothelioma is an aggressive and lethal tumour strongly associated with exposure to asbestos (mainly occupational). In Italy a large proportion of workers are protected from occupational diseases by public insurance and an epidemiological surveillance system for incident mesothelioma cases.</p> <p>Methods</p> <p>We set up an individual linkage between the Italian national mesothelioma register (ReNaM) and the Italian workers’ compensation authority (INAIL) archives. Logistic regression models were used to identify and test explanatory variables.</p> <p>Results</p> <p>We extracted 3270 mesothelioma cases with occupational origins from the ReNaM, matching them with 1625 subjects in INAIL (49.7%); 91.2% (1,482) of the claims received compensation. The risk of not seeking compensation is significantly higher for women and the elderly. Claims have increased significantly in recent years and there is a clear geographical gradient (northern and more developed regions having higher claims rates). The highest rates of compensation claims were after work known to involve asbestos.</p> <p>Conclusions</p> <p>Our data illustrate the importance of documentation and dissemination of all asbestos exposure modalities. Strategies focused on structural and systematic interaction between epidemiological surveillance and insurance systems are needed.</p

Malignant mesothelioma

Malignant mesothelioma is a fatal asbestos-associated malignancy originating from the lining cells (mesothelium) of the pleural and peritoneal cavities, as well as the pericardium and the tunica vaginalis. The exact prevalence is unknown but it is estimated that mesotheliomas represent less than 1% of all cancers. Its incidence is increasing, with an expected peak in the next 10–20 years. Pleural malignant mesothelioma is the most common form of mesothelioma. Typical presenting features are those of chest pain and dyspnoea. Breathlessness due to a pleural effusion without chest pain is reported in about 30% of patients. A chest wall mass, weight loss, sweating, abdominal pain and ascites (due to peritoneal involvement) are less common presentations. Mesothelioma is directly attributable to occupational asbestos exposure with a history of exposure in over 90% of cases. There is also evidence that mesothelioma may result from both para-occupational exposure and non-occupational "environmental" exposure. Idiopathic or spontaneous mesothelioma can also occur in the absence of any exposure to asbestos, with a spontaneous rate in humans of around one per million. A combination of accurate exposure history, along with examination radiology and pathology are essential to make the diagnosis. Distinguishing malignant from benign pleural disease can be challenging. The most helpful CT findings suggesting malignant pleural disease are 1) a circumferential pleural rind, 2) nodular pleural thickening, 3) pleural thickening of > 1 cm and 4) mediastinal pleural involvement. Involvement of a multidisciplinary team is recommended to ensure prompt and appropriate management, using a framework of radiotherapy, chemotherapy, surgery and symptom palliation with end of life care. Compensation issues must also be considered. Life expectancy in malignant mesothelioma is poor, with a median survival of about one year following diagnosis