Gene Function Classification Using Bayesian Models with Hierarchy-Based Priors

We investigate the application of hierarchical classification schemes to the annotation of gene function based on several characteristics of protein sequences including phylogenic descriptors, sequence based attributes, and predicted secondary structure. We discuss three Bayesian models and compare their performance in terms of predictive accuracy. These models are the ordinary multinomial logit (MNL) model, a hierarchical model based on a set of nested MNL models, and a MNL model with a prior that introduces correlations between the parameters for classes that are nearby in the hierarchy. We also provide a new scheme for combining different sources of information. We use these models to predict the functional class of Open Reading Frames (ORFs) from the E. coli genome. The results from all three models show substantial improvement over previous methods, which were based on the C5 algorithm. The MNL model using a prior based on the hierarchy outperforms both the non-hierarchical MNL model and the nested MNL model. In contrast to previous attempts at combining these sources of information, our approach results in a higher accuracy rate when compared to models that use each data source alone. Together, these results show that gene function can be predicted with higher accuracy than previously achieved, using Bayesian models that incorporate suitable prior information

Identifying people at higher risk of melanoma across the U.K.: a primary-care-based electronic survey

BACKGROUND: Melanoma incidence is rising rapidly worldwide among white populations. Defining higher-risk populations using risk prediction models may help targeted screening and early detection approaches. OBJECTIVES: To assess the feasibility of identifying people at higher risk of melanoma using the Williams self-assessed clinical risk estimation model in U.K. primary care. METHODS: We recruited participants from the waiting rooms of 22 general practices covering a total population of > 240 000 in three U.K. regions: Eastern England, North East Scotland and North Wales. Participants completed an electronic questionnaire using tablet computers. The main outcome was the mean melanoma risk score using the Williams melanoma risk model. RESULTS: Of 9004 people approached, 7742 (86%) completed the electronic questionnaire. The mean melanoma risk score for the 7566 eligible participants was 17·15 ± 8·51, with small regional differences [lower in England compared with Scotland (P = 0·001) and Wales (P < 0·001), mainly due to greater freckling and childhood sunburn among Scottish and Welsh participants]. After weighting to the age and sex distribution, different potential cut-offs would allow between 4% and 20% of the population to be identified as higher risk, and those groups would contain 30% and 60%, respectively of those likely to develop melanoma. CONCLUSIONS: Collecting data on the melanoma risk profile of the general population in U.K. primary care is both feasible and acceptable for patients in a general practice setting, and provides opportunities for new methods of real-time risk assessment and risk stratified cancer interventions

Modelling the lifetime cost-effectiveness of radical prostatectomy, radiotherapy and active monitoring for men with clinically localised prostate cancer from median 10-year outcomes in the ProtecT randomised trial.

BACKGROUND: Optimal management strategies for clinically localised prostate cancer are debated. Using median 10-year data from the largest randomised controlled trial to date (ProtecT), the lifetime cost-effectiveness of three major treatments (radical radiotherapy, radical prostatectomy and active monitoring) was explored according to age and risk subgroups. METHODS: A decision-analytic (Markov) model was developed and informed by clinical input. The economic evaluation adopted a UK NHS perspective and the outcome was cost per Quality-Adjusted Life Year (QALY) gained (reported in UK£), estimated using EQ-5D-3L. RESULTS: Costs and QALYs extrapolated over the lifetime were mostly similar between the three randomised strategies and their subgroups, but with some important differences. Across all analyses, active monitoring was associated with higher costs, probably associated with higher rates of metastatic disease and changes to radical treatments. When comparing the value of the strategies (QALY gains and costs) in monetary terms, for both low-risk prostate cancer subgroups, radiotherapy generated the greatest net monetary benefit (£293,446 [95% CI £282,811 to £299,451] by D'Amico and £292,736 [95% CI £284,074 to £297,719] by Grade group 1). However, the sensitivity analysis highlighted uncertainty in the finding when stratified by Grade group, as radiotherapy had 53% probability of cost-effectiveness and prostatectomy had 43%. In intermediate/high risk groups, using D'Amico and Grade group > = 2, prostatectomy generated the greatest net monetary benefit (£275,977 [95% CI £258,630 to £285,474] by D'Amico and £271,933 [95% CI £237,864 to £287,784] by Grade group). This finding was supported by the sensitivity analysis. Prostatectomy had the greatest net benefit (£290,487 [95% CI £280,781 to £296,281]) for men younger than 65 and radical radiotherapy (£201,311 [95% CI £195,161 to £205,049]) for men older than 65, but sensitivity analysis showed considerable uncertainty in both findings. CONCLUSION: Over the lifetime, extrapolating from the ProtecT trial, radical radiotherapy and prostatectomy appeared to be cost-effective for low risk prostate cancer, and radical prostatectomy for intermediate/high risk prostate cancer, but there was uncertainty in some estimates. Longer ProtecT trial follow-up is required to reduce uncertainty in the model. TRIAL REGISTRATION: Current Controlled Trials number, ISRCTN20141297: http://isrctn.org (14/10/2002); ClinicalTrials.gov number, NCT02044172: http://www.clinicaltrials.gov (23/01/2014)

Outcomes of a state-wide salt reduction initiative in adults living in Victoria, Australia

Purpose: To assess any effects of a state-wide sodium reduction intervention on sodium intake, sources of dietary sodium and discretionary salt use at a population level. Methods: Data (24-h urinary sodium excretion, self-report survey, a 24-h dietary recall) were collected cross-sectionally at baseline (2016/2017) and follow-up (2020) from adults in Victoria, Australia. Intervention activities included consumer awareness advertising campaign, public debate generation via mass media, strengthening existing policy initiatives and supporting food innovation with industry. Results: There were 339 participants at baseline and 211 at follow-up, with 144 and 90 of participants completing a 24-h dietary recall, respectively. There was no difference in adjusted 24-h urinary sodium excretion between baseline and follow-up (134 vs 131 mmol/24 h; p = 0.260). There were no differences in the percentage of participants adding salt during cooking (63% vs 68%; p = 0.244), adding salt at the table (34% vs 37%; p = 0.400) or regularly taking action to control salt/sodium intake (22% vs 21%; p = 0.793). There were large differences in the quantity of dietary sodium sourced from retail stores (57% vs 77%, p < 0.001), and less sodium was sourced from foods at fresh food markets (13% vs 2%; p ≤ 0.001) at follow-up. No large differences were apparent for foods with different levels of processing or for food groups. Conclusion: There was no clear population-level effect of the 4-year multi-component Victorian Salt Reduction Intervention on sodium intake with Victorian adults continuing to consume sodium above recommended levels. The findings indicate that more intensive and sustained efforts aiming at the retail and food industry with national level support are likely to be required to achieve a measurable improvement in sodium intake at a state level

Men's experiences of radiotherapy treatment for localized prostate cancer and its long-term treatment side effects: a longitudinal qualitative study.

PURPOSE: To investigate men's experiences of receiving external-beam radiotherapy (EBRT) with neoadjuvant Androgen Deprivation Therapy (ADT) for localized prostate cancer (LPCa) in the ProtecT trial. METHODS: A longitudinal qualitative interview study was embedded in the ProtecT RCT. Sixteen men with clinically LPCa who underwent EBRT in ProtecT were purposively sampled to include a range of socio-demographic and clinical characteristics. They participated in serial in-depth qualitative interviews for up to 8 years post-treatment, exploring experiences of treatment and its side effects over time. RESULTS: Men experienced bowel, sexual, and urinary side effects, mostly in the short term but some persisted and were bothersome. Most men downplayed the impacts, voicing expectations of age-related decline, and normalizing these changes. There was some reticence to seek help, with men prioritizing their relationships and overall health and well-being over returning to pretreatment levels of function. Some unmet needs with regard to information about treatment schedules and side effects were reported, particularly among men with continuing functional symptoms. CONCLUSIONS: These findings reinforce the importance of providing universal clear, concise, and timely information and supportive resources in the short term, and more targeted and detailed information and care in the longer term to maintain and improve treatment experiences for men undergoing EBRT

Adverse prognostic and predictive significance of low DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression in early-stage breast cancers

Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a serine threonine kinase belonging to the PIKK family (phosphoinositide 3-kinase-like-family of protein kinase), is a critical component of the non-homologous end joining (NHEJ) pathway required for the repair of DNA double strand breaks. DNA-PKcs may be involved in breast cancer pathogenesis. Methods: We evaluated clinicopathological significance of DNA-PKcs protein expression in 1161 tumours and DNA-PKcs mRNA expression in 1950 tumours. We correlated DNA-PKcs to other markers of aggressive phenotypes, DNA repair, apoptosis and cell cycle regulation. Results: Low DNA-PKcs protein expression was associated with higher tumour grade, higher mitotic index, tumour de-differentiation and tumour type (ps<0.05). Absence of BRCA1, low XRCC1/SMUG1/APE1/Polβ were also more likely in low DNA-PKcs expressing tumours (ps<0.05). Low DNA-PKcs protein expression was significantly associated with worse breast cancer specific survival (BCCS) in univariate and multivariate analysis (ps<0.01). At the mRNA level, low DNA-PKcs was associated with PAM50.Her2 and PAM50.LumA molecular phenotypes (ps<0.01) and poor BCSS. In patients with ER positive tumours who received endocrine therapy, low DNA-PKcs (protein and mRNA) was associated with poor survival. In ER negative patients, low DNA-PKcs mRNA remains significantly associated with adverse outcome. Conclusions: Our study suggests that low DNA-PKcs expression may have prognostic and predictive significance in breast cancers

Characteristics of men responding to an invitation to undergo testing for prostate cancer as part of a randomised trial

Background: Sociodemographic characteristics are associated with participating in cancer screening and trials. We compared the characteristics of those responding with those not responding to a single invitation for prostate-specific antigen (PSA) testing for prostate cancer as part of the Cluster randomised triAl of PSA testing for Prostate cancer (CAP). / Methods: Age, rurality and deprivation among 197,763 men from 271 cluster-randomised primary care centres in the UK were compared between those responding (n = 90,300) and those not responding (n = 100,953) to a prostate cancer testing invitation. / Results: There was little difference in age between responders and nonresponders. Responders were slightly more likely to come from urban rather than rural areas and were slightly less deprived than those who did not respond. / Conclusion: These data indicate similarities in age and only minor differences in deprivation and urban location between responders and nonresponders. These differences were smaller, but in the same direction as those observed in other screening trials. / Trial registration: ISRCTN92187251. Registered on 29 November 2004

Efficacy of bacterial ribosomal RNA-targeted reverse transcription-quantitative PCR for detecting neonatal sepsis: a case control study

<p>Abstract</p> <p>Background</p> <p>Neonatal sepsis is difficult to diagnose and pathogens cannot be detected from blood cultures in many cases. Development of a rapid and accurate method for detecting pathogens is thus essential. The main purpose of this study was to identify etiological agents in clinically diagnosed neonatal sepsis using bacterial ribosomal RNA-targeted reverse transcription-quantitative PCR (BrRNA-RT-qPCR) and to conduct comparisons with the results of conventional blood culture. Since BrRNA-RT-qPCR targets bacterial ribosomal RNA, detection rates using this approach may exceed those using conventional PCR.</p> <p>Methods</p> <p>Subjects comprised 36 patients with 39 episodes of suspected neonatal sepsis who underwent BrRNA-RT-qPCR and conventional blood culture to diagnose sepsis. Blood samples were collected aseptically for BrRNA-RT-qPCR and blood culture at the time of initial sepsis evaluation by arterial puncture. BrRNA-RT-qPCR and blood culture were undertaken using identical blood samples, and BrRNA-RT-qPCR was performed using 12 primer sets.</p> <p>Results</p> <p>Positive rate was significantly higher for BrRNA-RT-qPCR (15/39, 38.5%) than for blood culture (6/39, 15.4%; p = 0.0039). BrRNA-RT-qPCR was able to identify all pathogens detected by blood culture. Furthermore, this method detected pathogens from neonates with clinical sepsis in whom pathogens was not detected by culture methods.</p> <p>Conclusions</p> <p>This RT-PCR technique is useful for sensitive detection of pathogens causing neonatal sepsis, even in cases with negative results by blood culture.</p

Evaluation of a Salt-Reduction Consumer Awareness Campaign Targeted at Parents Residing in the State of Victoria, Australia

From 2015 to 2020 a state-wide salt-reduction initiative was launched in Victoria, Australia, including an awareness campaign focused on parents with children <18 years of age. To evaluate the impact of the campaign on salt-related knowledge, attitudes and behaviors (KABs) we have assessed trends in salt-related KAB pre- and post-delivery of the campaign in parents, as well as within the wider adult population. Cross-sectional surveys of adults aged 18–65 years were undertaken pre- (2015: n = 821 parents; n = 1527 general sample) and post-campaign (2019: n = 935 parents; n = 1747 general sample). KABs were assessed via an online survey. Data were analyzed with regression models and adjusted for covariates. Among parents, around one-quarter of salt-related KABs shifted in a positive direction, but changes were small: there was a 6% (95% CI 2, 11%) increase in the percentage who knew the main source of salt in the diet and reductions in the percentage who reported placing a salt shaker on the table (−8% (95%CI −12, −3)) and that their child added salt at the table (−5% (95% −9, −0.2)). Among the wider adult sample, even fewer shifts in KAB were observed, with some behaviors worsening at follow-up. These findings indicate that this consumer awareness campaign had minimum impact