Bayesian protein sequence and structure alignment

The structure of a protein is crucial in determining its functionality and is much more conserved than sequence during evolution. A key task in structural biology is to compare protein structures to determine evolutionary relationships, to estimate the function of newly discovered structures and to predict unknown structures. We propose a Bayesian method for protein structure alignment, with the prior on alignments based on functions which penalize ‘gaps’ in the aligned sequences. We show how a broad class of penalty functions fits into this framework, and how the resulting posterior distribution can be efficiently sampled. A commonly used gap penalty function is shown to be a special case, and we propose a new penalty function which alleviates an undesirable feature of the commonly used penalty. We illustrate our method on benchmark data sets and find that it competes well with popular tools from computational biology. Our method has the benefit of being able potentially to explore multiple competing alignments and to quantify their merits probabilistically. The framework naturally enables further information such as amino acid sequence to be included and could be adapted to other situations such as flexible proteins or domain swaps

Online dietary intake estimation : Reproducibility and validity of the Food4Me food frequency questionnaire against a 4-day weighed food record

©Rosalind Fallaize, Hannah Forster, Anna L Macready, Marianne C Walsh, John C Mathers, Lorraine Brennan, Eileen R Gibney, Michael J Gibney, Julie A Lovegrove. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 11.08.2014. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in the Journal of Medical Internet Research, is properly cited. The complete bibliographic information, a link to the original publication on http://www.jmir.org/, as well as this copyright and license information must be included.Background: Advances in nutritional assessment are continuing to embrace developments in computer technology. The online Food4Me food frequency questionnaire (FFQ) was created as an electronic system for the collection of nutrient intake data. To ensure its accuracy in assessing both nutrient and food group intake, further validation against data obtained using a reliable, but independent, instrument and assessment of its reproducibility are required. Objective: The aim was to assess the reproducibility and validity of the Food4Me FFQ against a 4-day weighed food record (WFR). Methods: Reproducibility of the Food4Me FFQ was assessed using test-retest methodology by asking participants to complete the FFQ on 2 occasions 4 weeks apart. To assess the validity of the Food4Me FFQ against the 4-day WFR, half the participants were also asked to complete a 4-day WFR 1 week after the first administration of the Food4Me FFQ. Level of agreement between nutrient and food group intakes estimated by the repeated Food4Me FFQ and the Food4Me FFQ and 4-day WFR were evaluated using Bland-Altman methodology and classification into quartiles of daily intake. Crude unadjusted correlation coefficients were also calculated for nutrient and food group intakes. Results: In total, 100 people participated in the assessment of reproducibility (mean age 32, SD 12 years), and 49 of these (mean age 27, SD 8 years) also took part in the assessment of validity. Crude unadjusted correlations for repeated Food4Me FFQ ranged from .65 (vitamin D) to .90 (alcohol). The mean cross-classification into "exact agreement plus adjacent" was 92% for both nutrient and food group intakes, and Bland-Altman plots showed good agreement for energy-adjusted macronutrient intakes. Agreement between the Food4Me FFQ and 4-day WFR varied, with crude unadjusted correlations ranging from .23 (vitamin D) to .65 (protein, % total energy) for nutrient intakes and .11 (soups, sauces and miscellaneous foods) to .73 (yogurts) for food group intake. The mean cross-classification into "exact agreement plus adjacent" was 80% and 78% for nutrient and food group intake, respectively. There were no significant differences between energy intakes estimated using the Food4Me FFQ and 4-day WFR, and Bland-Altman plots showed good agreement for both energy and energy-controlled nutrient intakes. Conclusions: The results demonstrate that the online Food4Me FFQ is reproducible for assessing nutrient and food group intake and has moderate agreement with the 4-day WFR for assessing energy and energy-adjusted nutrient intakes. The Food4Me FFQ is a suitable online tool for assessing dietary intake in healthy adults.Peer reviewedFinal Published versio

Effects of a web-based personalized intervention on physical activity in European adults: a randomized controlled trial

Background: The high prevalence of physical inactivity worldwide calls for innovative and more effective ways to promote physical activity (PA). There are limited objective data on the effectiveness of Web-based personalized feedback on increasing PA in adults. Objective: It is hypothesized that providing personalized advice based on PA measured objectively alongside diet, phenotype, or genotype information would lead to larger and more sustained changes in PA, compared with nonpersonalized advice. Methods: A total of 1607 adults in seven European countries were randomized to either a control group (nonpersonalized advice, Level 0, L0) or to one of three personalized groups receiving personalized advice via the Internet based on current PA plus diet (Level 1, L1), PA plus diet and phenotype (Level 2, L2), or PA plus diet, phenotype, and genotype (Level 3, L3). PA was measured for 6 months using triaxial accelerometers, and self-reported using the Baecke questionnaire. Outcomes were objective and self-reported PA after 3 and 6 months. Results: While 1270 participants (85.81% of 1480 actual starters) completed the 6-month trial, 1233 (83.31%) self-reported PA at both baseline and month 6, but only 730 (49.32%) had sufficient objective PA data at both time points. For the total cohort after 6 months, a greater improvement in self-reported total PA (P=.02) and PA during leisure (nonsport) (P=.03) was observed in personalized groups compared with the control group. For individuals advised to increase PA, we also observed greater improvements in those two self-reported indices (P=.006 and P=.008, respectively) with increased personalization of the advice (L2 and L3 vs L1). However, there were no significant differences in accelerometer results between personalized and control groups, and no significant effect of adding phenotypic or genotypic information to the tailored feedback at month 3 or 6. After 6 months, there were small but significant improvements in the objectively measured physical activity level (P<.05), moderate PA (P<.01), and sedentary time (P<.001) for individuals advised to increase PA, but these changes were similar across all groups. Conclusions: Different levels of personalization produced similar small changes in objective PA. We found no evidence that personalized advice is more effective than conventional “one size fits all” guidelines to promote changes in PA in our Web-based intervention when PA was measured objectively. Based on self-reports, PA increased to a greater extent with more personalized advice. Thus, it is crucial to measure PA objectively in any PA intervention study

Changes in physical activity following a genetic-based internet-delivered personalized intervention: randomized controlled trial (Food4Me)

Background: There is evidence that physical activity (PA) can attenuate the influence of the fat mass- and obesity-associated (FTO) genotype on the risk to develop obesity. However, whether providing personalized information on FTO genotype leads to changes in PA is unknown. Objective: The purpose of this study was to determine if disclosing FTO risk had an impact on change in PA following a 6-month intervention. Methods: The single nucleotide polymorphism (SNP) rs9939609 in the FTO gene was genotyped in 1279 participants of the Food4Me study, a four-arm, Web-based randomized controlled trial (RCT) in 7 European countries on the effects of personalized advice on nutrition and PA. PA was measured objectively using a TracmorD accelerometer and was self-reported using the Baecke questionnaire at baseline and 6 months. Differences in baseline PA variables between risk (AA and AT genotypes) and nonrisk (TT genotype) carriers were tested using multiple linear regression. Impact of FTO risk disclosure on PA change at 6 months was assessed among participants with inadequate PA, by including an interaction term in the model: disclosure (yes/no) × FTO risk (yes/no). Results: At baseline, data on PA were available for 874 and 405 participants with the risk and nonrisk FTO genotypes, respectively. There were no significant differences in objectively measured or self-reported baseline PA between risk and nonrisk carriers. A total of 807 (72.05%) of the participants out of 1120 in the personalized groups were encouraged to increase PA at baseline. Knowledge of FTO risk had no impact on PA in either risk or nonrisk carriers after the 6-month intervention. Attrition was higher in nonrisk participants for whom genotype was disclosed (P=.01) compared with their at-risk counterparts. Conclusions: No association between baseline PA and FTO risk genotype was observed. There was no added benefit of disclosing FTO risk on changes in PA in this personalized intervention. Further RCT studies are warranted to confirm whether disclosure of nonrisk genetic test results has adverse effects on engagement in behavior change

Objectively measured physical activity in European adults: cross-sectional findings from the Food4Me study

Background Comparisons of objectively measured physical activity (PA) between residents of European countries measured concurrently with the same protocol are lacking. We aimed to compare PA between the seven European countries involved in the Food4Me Study, using accelerometer data collected remotely via the Internet. Methods Of the 1607 participants recruited, 1287 (539 men and 748 women) provided at least 3 weekdays and 2 weekend days of valid accelerometer data (TracmorD) at baseline and were included in the present analyses. Results Men were significantly more active than women (physical activity level = 1.74 vs. 1.70, p < 0.001). Time spent in light PA and moderate PA differed significantly between countries but only for women. Adherence to the World Health Organization recommendation to accumulate at least 150 min of moderate-equivalent PA weekly was similar between countries for men (range: 54–65%) but differed significantly between countries for women (range: 26–49%). Prevalence estimates decreased substantially for men and women in all seven countries when PA guidelines were defined as achieving 30 min of moderate and vigorous PA per day. Conclusions We were able to obtain valid accelerometer data in real time via the Internet from 80% of participants. Although our estimates are higher compared with data from Sweden, Norway, Portugal and the US, there is room for improvement in PA for all countries involved in the Food4Me Study

Outcomes of obstructed abdominal wall hernia: results from the UK national small bowel obstruction audit

Background: Abdominal wall hernia is a common surgical condition. Patients may present in an emergency with bowel obstruction, incarceration or strangulation. Small bowel obstruction (SBO) is a serious surgical condition associated with significant morbidity. The aim of this study was to describe current management and outcomes of patients with obstructed hernia in the UK as identified in the National Audit of Small Bowel Obstruction (NASBO). Methods: NASBO collated data on adults treated for SBO at 131 UK hospitals between January and March 2017. Those with obstruction due to abdominal wall hernia were included in this study. Demographics, co-morbidity, imaging, operative treatment, and in-hospital outcomes were recorded. Modelling for factors associated with mortality and complications was undertaken using Cox proportional hazards and multivariable regression modelling. Results: NASBO included 2341 patients, of whom 415 (17·7 per cent) had SBO due to hernia. Surgery was performed in 312 (75·2 per cent) of the 415 patients; small bowel resection was required in 198 (63·5 per cent) of these operations. Non-operative management was reported in 35 (54 per cent) of 65 patients with a parastomal hernia and in 34 (32·1 per cent) of 106 patients with an incisional hernia. The in-hospital mortality rate was 9·4 per cent (39 of 415), and was highest in patients with a groin hernia (11·1 per cent, 17 of 153). Complications were common, including lower respiratory tract infection in 16·3 per cent of patients with a groin hernia. Increased age was associated with an increased risk of death (hazard ratio 1·05, 95 per cent c.i. 1·01 to 1·10; P = 0·009) and complications (odds ratio 1·05, 95 per cent c.i. 1·02 to 1·09; P = 0·001). Conclusion: NASBO has highlighted poor outcomes for patients with SBO due to hernia, highlighting the need for quality improvement initiatives in this group

Outcomes of obstructed abdominal wall hernia: results from the UK national small bowel obstruction audit

Background Abdominal wall hernia is a common surgical condition. Patients may present in an emergency with bowel obstruction, incarceration or strangulation. Small bowel obstruction (SBO) is a serious surgical condition associated with significant morbidity. The aim of this study was to describe current management and outcomes of patients with obstructed hernia in the UK as identified in the National Audit of Small Bowel Obstruction (NASBO). Methods NASBO collated data on adults treated for SBO at 131 UK hospitals between January and March 2017. Those with obstruction due to abdominal wall hernia were included in this study. Demographics, co‐morbidity, imaging, operative treatment, and in‐hospital outcomes were recorded. Modelling for factors associated with mortality and complications was undertaken using Cox proportional hazards and multivariable regression modelling. Results NASBO included 2341 patients, of whom 415 (17·7 per cent) had SBO due to hernia. Surgery was performed in 312 (75·2 per cent) of the 415 patients; small bowel resection was required in 198 (63·5 per cent) of these operations. Non‐operative management was reported in 35 (54 per cent) of 65 patients with a parastomal hernia and in 34 (32·1 per cent) of 106 patients with an incisional hernia. The in‐hospital mortality rate was 9·4 per cent (39 of 415), and was highest in patients with a groin hernia (11·1 per cent, 17 of 153). Complications were common, including lower respiratory tract infection in 16·3 per cent of patients with a groin hernia. Increased age was associated with an increased risk of death (hazard ratio 1·05, 95 per cent c.i. 1·01 to 1·10; P = 0·009) and complications (odds ratio 1·05, 95 per cent c.i. 1·02 to 1·09; P = 0·001). Conclusion NASBO has highlighted poor outcomes for patients with SBO due to hernia, highlighting the need for quality improvement initiatives in this group

Bayesian alignment of similarity shapes

We develop a Bayesian model for the alignment of two point configurations under the full similarity transformations of rotation, translation and scaling. Other work in this area has concentrated on rigid body transformations, where scale information is preserved, motivated by problems involving molecular data; this is known as form analysis.We concentrate on a Bayesian formulation for statistical shape analysis.We generalize the model introduced by Green and Mardia [Biometrika 93 (2006) 235-254] for the pairwise alignment of two unlabeled configurations to full similarity transformations by introducing a scaling factor to the model. The generalization is not straightforward, since the model needs to be reformulated to give good performance when scaling is included. We illustrate our method on the alignment of rat growth profiles and a novel application to the alignment of protein domains. Here, scaling is applied to secondary structure elements when comparing protein folds; additionally, we find that one global scaling factor is not in general sufficient to model these data and, hence, we develop a model in which multiple scale factors can be included to handle different scalings of shape components

Hierarchical bayesian modeling of pharmacophores in bioinformatics

One of the key ingredients in drug discovery is the derivation of conceptual templates called pharmacophores. A pharmacophore model characterizes the physicochemical properties common to all active molecules, called ligands, bound to a particular protein receptor, together with their relative spatial arrangement. Motivated by this important application, we develop a Bayesian hierarchical model for the derivation of pharmacophore templates from multiple configurations of point sets, partially labeled by the atom type of each point. The model is implemented through a multistage template hunting algorithm that produces a series of templates that capture the geometrical relationship of atoms matched across multiple configurations. Chemical information is incorporated by distinguishing between atoms of different elements, whereby different elements are less likely to be matched than atoms of the same element. We illustrate our method through examples of deriving templates from sets of ligands that all bind structurally related protein active sites and show that the model is able to retrieve the key pharmacophore features in two test cases