Actigraphy-derived measures of sleep and risk of prostate cancer in the UK Biobank.

BACKGROUND: Studies of sleep and prostate cancer are almost entirely based on self-report, with limited research using actigraphy. Our goal was to evaluate actigraphy-measured sleep and prostate cancer and to expand on findings from prior studies of self-reported sleep. METHODS: We prospectively examined 34 260 men without a history of prostate cancer in the UK Biobank. Sleep characteristics were measured over 7 days using actigraphy. We calculated sleep duration, onset, midpoint, wake-up time, social jetlag (difference in weekend-weekday sleep midpoints), sleep efficiency (percentage of time spent asleep between onset and wake-up time), and wakefulness after sleep onset. Cox proportional hazards models were used to estimate covariate-adjusted hazards ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Over 7.6 years, 1152 men were diagnosed with prostate cancer. Sleep duration was not associated with prostate cancer risk. Sleep midpoint earlier than 4:00 am was not associated with prostate cancer risk, though sleep midpoint of 5:00 am or later was suggestively associated with lower prostate cancer risk but had limited precision (earlier than 4:00 am vs 4:00-4:59 am HR = 1.00, 95% CI = 0.87 to 1.16; 5:00 am or later vs 4:00-4:59 am HR = 0.79, 95% CI = 0.57 to 1.10). Social jetlag was not associated with greater prostate cancer risk (1 to <2 hours vs <1 hour HR = 1.06, 95% CI = 0.89 to 1.25; ≥2 hours vs <1 hour HR = 0.90, 95% CI = 0.65 to 1.26). Compared with men who averaged less than 30 minutes of wakefulness after sleep onset per day, men with 60 minutes or more had a higher risk of prostate cancer (HR = 1.20, 95% CI = 1.00 to 1.43). CONCLUSIONS: Of the sleep characteristics studied, higher wakefulness after sleep onset-a measure of poor sleep quality-was associated with greater prostate cancer risk. Replication of our findings between wakefulness after sleep onset and prostate cancer are warranted.

Quest markup for developing FAIR questionnaire modules for epidemiologic studies.

BACKGROUND: Online questionnaires are commonly used to collect information from participants in epidemiological studies. This requires building questionnaires using machine-readable formats that can be delivered to study participants using web-based technologies such as progressive web applications. However, the paucity of open-source markup standards with support for complex logic make collaborative development of web-based questionnaire modules difficult. This often prevents interoperability and reusability of questionnaire modules across epidemiological studies. RESULTS: We developed an open-source markup language for presentation of questionnaire content and logic, Quest, within a real-time renderer that enables the user to test logic (e.g., skip patterns) and view the structure of data collection. We provide the Quest markup language, an in-browser markup rendering tool, questionnaire development tool and an example web application that embeds the renderer, developed for The Connect for Cancer Prevention Study. CONCLUSION: A markup language can specify both the content and logic of a questionnaire as plain text. Questionnaire markup, such as Quest, can become a standard format for storing questionnaires or sharing questionnaires across the web. Quest is a step towards generation of FAIR data in epidemiological studies by facilitating reusability of questionnaires and data interoperability using open-source tools.

Smoking status, usual adult occupation, and risk of recurrent urothelial bladder carcinoma: data from The Cancer Genome Atlas (TCGA) Project.

PURPOSE: Tobacco smoking and occupational exposures are the leading risk factors for developing urothelial bladder carcinoma (UBC), yet little is known about the contribution of these two factors to risk of UBC recurrence. We evaluated whether smoking status and usual adult occupation are associated with time to UBC recurrence for 406 patients with muscle-invasive bladder cancer submitted to The Cancer Genome Atlas (TCGA) project. METHODS: Kaplan-Meier and Cox proportional hazard methods were used to assess the association between smoking status, employment in a high-risk occupation for bladder cancer, occupational diesel exhaust exposure, and 2010 Standard Occupational Classification group and time to UBC recurrence. RESULTS: Data on time to recurrence were available for 358 patients over a median follow-up time of 15 months. Of these, 133 (37.2%) experienced a recurrence. Current smokers who smoked for more than 40 pack-years had an increased risk of recurrence compared to never smokers (HR 2.1, 95% CI 1.1, 4.1). Additionally, employment in a high-risk occupation was associated with a shorter time to recurrence (log-rank p = 0.005). We found an increased risk of recurrence for those employed in occupations with probable diesel exhaust exposure (HR 1.8, 95% CI 1.1, 3.0) and for those employed in production occupations (HR 2.0, 95% CI 1.1, 3.6). CONCLUSIONS: These findings suggest smoking status impacts risk of UBC recurrence, although several previous studies provided equivocal evidence regarding this association. In addition to the known causal relationship between occupational exposure and bladder cancer risk, our study suggests that occupation may also be related to increased risk of recurrence.

Computer-based coding of free-text job descriptions to efficiently identify occupations in epidemiological studies.

BACKGROUND: Mapping job titles to standardised occupation classification (SOC) codes is an important step in identifying occupational risk factors in epidemiological studies. Because manual coding is time-consuming and has moderate reliability, we developed an algorithm called SOCcer (Standardized Occupation Coding for Computer-assisted Epidemiologic Research) to assign SOC-2010 codes based on free-text job description components. METHODS: Job title and task-based classifiers were developed by comparing job descriptions to multiple sources linking job and task descriptions to SOC codes. An industry-based classifier was developed based on the SOC prevalence within an industry. These classifiers were used in a logistic model trained using 14 983 jobs with expert-assigned SOC codes to obtain empirical weights for an algorithm that scored each SOC/job description. We assigned the highest scoring SOC code to each job. SOCcer was validated in 2 occupational data sources by comparing SOC codes obtained from SOCcer to expert assigned SOC codes and lead exposure estimates obtained by linking SOC codes to a job-exposure matrix. RESULTS: For 11 991 case-control study jobs, SOCcer-assigned codes agreed with 44.5% and 76.3% of manually assigned codes at the 6-digit and 2-digit level, respectively. Agreement increased with the score, providing a mechanism to identify assignments needing review. Good agreement was observed between lead estimates based on SOCcer and manual SOC assignments (κ 0.6-0.8). Poorer performance was observed for inspection job descriptions, which included abbreviations and worksite-specific terminology. CONCLUSIONS: Although some manual coding will remain necessary, using SOCcer may improve the efficiency of incorporating occupation into large-scale epidemiological studies.

Characterization of germline antibody libraries from human umbilical cord blood and selection of monoclonal antibodies to viral envelope glycoproteins: Implications for mechanisms of immune evasion and design of vaccine immunogens.

We have previously observed that all known HIV-1 broadly neutralizing antibodies (bnAbs) are highly divergent from germline antibodies in contrast to bnAbs against Hendra virus, Nipah virus and SARS coronavirus (SARS CoV). We have hypothesized that because the germline antibodies are so different from the mature HIV-1-specific bnAbs they may not bind the epitopes of the mature antibodies and provided the first evidence to support this hypothesis by using individual putative germline-like predecessor antibodies. To further validate the hypothesis and understand initial immune responses to different viruses, two phage-displayed human cord blood-derived IgM libraries were constructed which contained mostly germline antibodies or antibodies with very low level of somatic hypermutations. They were panned against different HIV-1 envelope glycoproteins (Envs), SARS CoV protein receptor-binding domain (RBD), and soluble Hendra virus G protein (sG). Despite a high sequence and combinatorial diversity observed in the cord blood-derived IgM antibody repertoire, no enrichment for binders of Envs was observed in contrast to considerable specific enrichments produced with panning against RBD and sG; one of the selected monoclonal antibodies (against the RBD) was of high (nM) affinity with only few somatic mutations. These results further support and expand our initial hypothesis for fundamental differences in immune responses leading to elicitation of bnAbs against HIV-1 compared to SARS CoV and Hendra virus. HIV-1 uses a strategy to minimize or eliminate strong binding of germline antibodies to its Env; in contrast, SARS CoV and Hendra virus, and perhaps other viruses causing acute infections, can bind germline antibody or minimally somatically mutated antibodies with relatively high affinity which could be one of the reasons for the success of sG and RBD as vaccine immunogens.

Analysis of somatic hypermutation in X-linked hyper-IgM syndrome shows specific deficiencies in mutational targeting.

Subjects with X-linked hyper-IgM syndrome (X-HIgM) have a markedly reduced frequency of CD27(+) memory B cells, and their Ig genes have a low level of somatic hypermutation (SHM). To analyze the nature of SHM in X-HIgM, we sequenced 209 nonproductive and 926 productive Ig heavy chain genes. In nonproductive rearrangements that were not subjected to selection, as well as productive rearrangements, most of the mutations were within targeted RGYW, WRCY, WA, or TW motifs (R = purine, Y = pyrimidine, and W = A or T). However, there was significantly decreased targeting of the hypermutable G in RGYW motifs. Moreover, the ratio of transitions to transversions was markedly increased compared with normal. Microarray analysis documented that specific genes involved in SHM, including activation-induced cytidine deaminase (AICDA) and uracil-DNA glycosylase (UNG2), were up-regulated in normal germinal center (GC) B cells, but not induced by CD40 ligation. Similar results were obtained from light chain rearrangements. These results indicate that in the absence of CD40-CD154 interactions, there is a marked reduction in SHM and, specifically, mutations of AICDA-targeted G residues in RGYW motifs along with a decrease in transversions normally related to UNG2 activity.