Shared Inherited Genetics of Benign Prostatic Hyperplasia and Prostate Cancer

BackgroundThe association between benign prostatic hyperplasia (BPH) and prostate cancer (PCa) remains controversial, largely due to inherent detection bias in traditional observational studies. The objective of this study is to assess their association using inherited SNPs.MethodsSubjects were White men from the large population-based UK Biobank (UKB). Association between BPH and PCa was tested: 1) phenotypical correlation using chi-square test, 2) genetic correlation (rg) based on 1,126,841 polymorphic SNPs across the genome using linkage disequilibrium score regression (LDSR), and 3) cross-disease genetic associations based on known risk-associated SNPs (15 for BPH and 239 for PCa), individually and cumulatively as measured by genetic risk score (GRS).FindingsAmong 214,717 White men in the UKB, 24,623 (11.47%) and 14,311 (6.67%) had a diagnosis of BPH and PCa, respectively. Diagnoses of these two diseases were significantly correlated, χ2=1862.80, P<1E-299. A significant genetic correlation was found, rg (95% confidence interval (CI))=0.27 (0.15-0.39), P=9.17E-06. In addition, significant cross-disease genetic associations for established risk-associated SNPs were also found. Among the 250 established GWAS-significant SNPs of PCa or BPH, 51 were significantly associated with risk of the other disease at P<0.05, significantly more than expected by chance (N=12), P=3.04E-7 (χ2-test). Furthermore, significant cross-disease GRS associations were also found; GRSBPH was significantly associated with PCa risk (odds ratio (OR)=1.26 (1.18-1.36), P=1.62E-10), and GRSPCa was significantly associated with BPH risk (OR=1.03 (1.02-1.04), P=8.57E-06). Moreover, GRSBPH was significantly and inversely associated with lethal PCa risk in a PCa case-case analysis (OR=0.58 (0.41-0.81), P=1.57E-03). In contrast, GRSPCa was not significantly associated with lethal PCa (OR=0.99 (0.94-1.04), P=0.79).InterpretationBPH and PCa share common inherited genetics which suggests the phenotypical association of these two diseases in observational studies is not entirely caused by detection bias. This novel finding may have implications in disease etiology and risk stratification.FundingNone.

Assessing the risk of performance and detection bias in Cochrane reviews as a joint domain is less accurate compared to two separate domains

Background Initially, the Cochrane risk of bias (RoB) tool had a domain for “blinding of participants, personnel and outcome assessors”. In the 2011 tool, the assessment of blinding was split into two domains: blinding of participants and personnel (performance bias) and blinding of outcome assessors (detection bias). The aims of this study were twofold; first, to analyze the frequency of usage of the joint blinding domain (a single domain for performance and detection bias), and second, to assess the proportion of adequate assessments made in the joint versus single RoB domains for blinding by comparing whether authors’ RoB judgments were supported by explanatory comments in line with the Cochrane Handbook recommendations. Methods We extracted information about the assessment of blinding from RoB tables (judgment, comment, and whether it was specified which outcome type; e.g., objective, subjective) of 729 Cochrane reviews published in 2015-2016. In the Cochrane RoB tool, judgment (low, unclear or high risk) needs to be accompanied by a transparent comment, in which authors provide a summary justifying RoB judgment, to ensure transparency in how these judgments were reached. We reassessed RoB based on the supporting comments reported in Cochrane RoB tables, in line with instructions from the Cochrane Handbook. Then, we compared our new assessments to judgments made by Cochrane authors. We compared the frequency of adequate judgments in reviews with two separate domains for blinding versus those with a joint domain for blinding. Results The total number of assessments for performance bias was 6918, with 8656 for detection bias and 3169 for the joint domain. The frequency of adequate assessments was 74% for performance bias, 78% for detection bias, and 59% for the joint domain. The lowest frequency of adequate assessments was found when Cochrane authors judged low risk – 47% in performance bias, 62% in detection bias, and 31% in the joint domain. The joint domain and detection bias domain had a similar proportion of specified outcome types (17% and 18%, respectively). Conclusions Splitting joint RoB assessment about blinding into two domains was justified because the frequency of adequate judgments was higher in separate domains. Specification of outcome types in RoB domains should be further scrutinized.

Calculation Methods of Solution Chemical Potential and Application in Emulsion Microencapsulation

Several new biased sampling methods were summarized for solution chemical potential calculation methods in the field of emulsion microencapsulation. The principles, features, and calculation efficiencies of various biased Widom insertion sampling methods were introduced, including volume detection bias, simulation ensemble bias, and particle insertion bias. The proper matches between various types of solution in emulsion and biased Widom methods were suggested, following detailed analyses on the biased insertion techniques. The volume detection bias methods effectively improved the accuracy of the data and the calculation efficiency by inserting detection particles and were suggested to be used for the calculation of solvent chemical potential for the homogeneous aqueous phase of the emulsion. The chemical potential of water, argon, and fluorobenzene (a typical solvent of the oil phase in double emulsion) was calculated by a new, optimized volume detection bias proposed by this work. The recently developed Well-Tempered(WT)-Metadynamics method skillfully constructed low-density regions for particle insertion and dynamically adjusted the system configuration according to the potential energy around the detection point, and hence, could be used for the oil-polymer mixtures of microencapsulation emulsion. For the macromolecule solutes in the oil or aqueous phase of the emulsion, the particle insertion bias could be applied to greatly increase the success rate of Widom insertions. Readers were expected to choose appropriate biased Widom methods to carry out their calculations on chemical potential, fugacity, and solubility of solutions based on the system molecular properties, inspired by this paper.

A Latent Disease Model to Reduce Detection Bias in Cancer Risk Prediction Studies

In studies of cancer risk, detection bias arises when risk factors are associated with screening patterns, affecting the likelihood and timing of diagnosis. To eliminate detection bias in a screened cohort, we propose modeling the latent onset of cancer and estimating the association between risk factors and onset rather than diagnosis. We apply this framework to estimate the increase in prostate cancer risk associated with black race and family history using data from the SELECT prostate cancer prevention trial, in which men were screened and biopsied according to community practices. A positive family history was associated with a hazard ratio (HR) of prostate cancer onset of 1.8, lower than the corresponding HR of prostate cancer diagnosis (HR = 2.2). This result comports with a finding that men in SELECT with a family history were more likely to be biopsied following a positive PSA test than men with no family history. For black race, the HRs for onset and diagnosis were similar, consistent with similar patterns of screening and biopsy by race. If individual screening and diagnosis histories are available, latent disease modeling can be used to decouple risk of disease from risk of disease diagnosis and reduce detection bias.

The Potential Influence of Absence of Blinding Method: Secondary Analysis From Randomized Controlled Trials Concerned Acupuncture for Depression

Background To evaluate the possibility and impact of performance and detection bias in randomized controlled trials due to lack of the blinding method. MethodsTrials assessing acupuncture for depression published by March 2020 were searched from China National Knowledge Infrastructure database. Through matching, we reassembled the trials of comparing experimental acupuncture and control acupuncture. Meta-analysis with post-treatment HAMD (Hamilton Depression Scale) of the newly reassembled trials was conducted. Changes of HAMD of all included groups were also analyzed, the between groups difference was then analyzed by t-test. All statistical analyses were performed using RevMan 5.3 software. ResultsThirteen pairs of studies were matched from 63 included trials. Re-analysis from the paired studies showed obvious difference of HAMD scales between the experimental and control acupuncture (Mean Difference was -2.95 for HAMD-17, -5.55 for HAMD-24). Re-analysis from all the included groups also showed the statistical difference between groups at four weeks of HAMD-17 (P=0.01), and four/six weeks of HAMD-24 (P<0.01).Conclusion Effectiveness of acupuncture for decreasing the severity of depression was superior in trials that considered acupuncture as experimental treatment, showing performance and detection bias caused by the absence of blinding method is of great significance in acupuncture trials.

Cancer Incidence and Mortality in the U.S. Astronaut Corps, 1959-2017

Background: Cancer incidence and mortality are important outcomes in the surveillance of long-term astronaut health. In this research, we compare cancer incidence rates, cancer-specific mortality rates, and cancer case fatality ratios in US astronauts with those in the US general population.Methods: We use standardized incidence ratios and standardized mortality ratios to index the incidence and mortality of various cancers against rates in the US general population, from the US astronaut cohort inception in April 1959 through 31 December 2017. We also compare the lethality of these cancers in astronauts and the general population using the relative case fatality ratio.Results: The astronaut cohort included 338 individuals and over 9600 person-years of follow-up time. The counts of most cancers were under 3, though there were 11 cases of melanoma and 30 cases of prostate cancer. Both prostate and melanoma had statistically significant increases in incidence, though only melanoma had a significant increase in mortality. Lung cancer had a statistically significant deficit of both cases and deaths, while colon cancer had sizable (but not statistically significant) reductions in incidence and mortality. Three cancers showed evidence of detection bias (colon, hematologic, prostate), possibly a result of astronaut health screening protocols. For all cancers combined, astronauts showed a non-significant reduction in incidence and mortality, and a significant reduction in case fatality ratio.Conclusions: Though there were observed increases in both incidence and mortality from melanoma among astronauts, these increases are consistent with those observed repeatedly among aircraft pilots, suggesting this may be associated with ultraviolet radiation or lifestyle factors rather than any astronaut-specific exposure. The increase in prostate cancer incidence is likely explained by detection bias, and the same may be true for hematologic cancers. The lack of statistical significance in the reduction of incidence and mortality for colon cancer may be attributable to relaxed screening practices for astronauts in recent years. As astronaut health surveillance continues and evolves, the growing database will lead to a clearer picture over time. The methods employed here provide a useful structure for ongoing analysis of this unique occupational cohort.