A comparison of internal validation techniques for multifactor dimensionality reduction

<p>Abstract</p> <p>Background</p> <p>It is hypothesized that common, complex diseases may be due to complex interactions between genetic and environmental factors, which are difficult to detect in high-dimensional data using traditional statistical approaches. Multifactor Dimensionality Reduction (MDR) is the most commonly used data-mining method to detect epistatic interactions. In all data-mining methods, it is important to consider internal validation procedures to obtain prediction estimates to prevent model over-fitting and reduce potential false positive findings. Currently, MDR utilizes cross-validation for internal validation. In this study, we incorporate the use of a three-way split (3WS) of the data in combination with a post-hoc pruning procedure as an alternative to cross-validation for internal model validation to reduce computation time without impairing performance. We compare the power to detect true disease causing loci using MDR with both 5- and 10-fold cross-validation to MDR with 3WS for a range of single-locus and epistatic disease models. Additionally, we analyze a dataset in HIV immunogenetics to demonstrate the results of the two strategies on real data.</p> <p>Results</p> <p>MDR with 3WS is computationally approximately five times faster than 5-fold cross-validation. The power to find the exact true disease loci without detecting false positive loci is higher with 5-fold cross-validation than with 3WS before pruning. However, the power to find the true disease causing loci in addition to false positive loci is equivalent to the 3WS. With the incorporation of a pruning procedure after the 3WS, the power of the 3WS approach to detect only the exact disease loci is equivalent to that of MDR with cross-validation. In the real data application, the cross-validation and 3WS analyses indicate the same two-locus model.</p> <p>Conclusions</p> <p>Our results reveal that the performance of the two internal validation methods is equivalent with the use of pruning procedures. The specific pruning procedure should be chosen understanding the trade-off between identifying all relevant genetic effects but including false positives and missing important genetic factors. This implies 3WS may be a powerful and computationally efficient approach to screen for epistatic effects, and could be used to identify candidate interactions in large-scale genetic studies.</p

PinR mediates the generation of reversible population diversity in Streptococcus zooepidemicus

Opportunistic pathogens must adapt to and survive in a wide range of complex ecosystems. Streptococcus zooepidemicus is an opportunistic pathogen of horses and many other animals, including humans. The assembly of different surface architecture phenotypes from one genotype is likely to be crucial to the successful exploitation of such an opportunistic lifestyle. Construction of a series of mutants revealed that a serine recombinase, PinR, inverts 114 bp of the promoter of SZO_08560, which is bordered by GTAGACTTTA and TAAAGTCTAC inverted repeats. Inversion acts as a switch, controlling the transcription of this sortase-processed protein, which may enhance the attachment of S. zooepidemicus to equine trachea. The genome of a recently sequenced strain of S. zooepidemicus, 2329 (Sz2329), was found to contain a disruptive internal inversion of 7 kb of the FimIV pilus locus, which is bordered by TAGAAA and TTTCTA inverted repeats. This strain lacks pinR and this inversion may have become irreversible following the loss of this recombinase. Active inversion of FimIV was detected in three strains of S. zooepidemicus, 1770 (Sz1770), B260863 (SzB260863) and H050840501 (SzH050840501), all of which encoded pinR. A deletion mutant of Sz1770 that lacked pinR was no longer capable of inverting its internal region of FimIV. The data highlight redundancy in the PinR sequence recognition motif around a short TAGA consensus and suggest that PinR can reversibly influence the wider surface architecture of S. zooepidemicus, providing this organism with a bet-hedging solution to survival in fluctuating environments

Implementing evidence-informed policy into practice for health care professionals managing people with low back pain in Australian rural settings: A preliminary prospective single-cohort study

Objective: To provide access to professional development opportunities for health care professionals, especially in rural Australian regions, consistent with recommendations in the Australian National Pain Strategy and state government policy. Design and Setting: A preliminary prospective, single-cohort study design, which aligned health policy with evidence-informed clinical practice, evaluated the implementation and effectiveness of an interprofessional, health care provider pain education program (hPEP) for management of nonspecific low back pain (nsLBP) in rural Western Australia. Intervention: The 6.5-hour hPEP intervention was delivered to 60 care providers (caseload nsLBP 19.8% ± 22.5) at four rural WA regions. Outcome Measures: Outcomes were recorded at baseline and 2 months post-intervention regarding attitudes, beliefs (modified Health Care Providers Pain and Impairment Relationship Scale [HC-PAIRS]), Back Pain Beliefs Questionnaire [BBQ]), and self-reported evidence-based clinical practice (knowledge and skills regarding nsLBP, rated on a 5-point Likert scale with 1 = nil and 5 = excellent).Results: hPEP was feasible to implement. At 2 months post-hPEP, responders' (response rate 53%) improved evidence-based beliefs were indicated by HC-PAIRS scores: baseline mean (SD) [43.2 (9.3)]; mean difference (95% CI) [−5.9 (−8.6 to −3.1)]; and BBQ baseline [34.3 (6.8)]; mean difference [2.1 (0.5 to 3.6)]. Positive shifts were observed for all measures of clinical knowledge and skills (P < 0.001) and increased assistance with planning lifestyle changes (P < 0.001), advice on self-management (P = 0.010), and for decreased referrals for spinal imaging (P = 0.03). Conclusions: This policy-into-practice educational program is feasible to implement in rural Western Australia (WA). While preliminary data are encouraging, a further randomized controlled trial is recommended

Estimating spring terminus submarine melt rates at a greenlandic tidewater glacier using satellite imagery

Oceanic forcing of the Greenland Ice Sheet is believed to promote widespread thinning at tidewater glaciers, with submarine melting proposed as a potential trigger of increased glacier calving, retreat, and subsequent acceleration. The precise mechanism(s) driving glacier instability, however, remain poorly understood, and while increasing evidence points to the importance of submarine melting, estimates of melt rates are uncertain. Here we estimate submarine melt rate by examining freeboard changes in the seasonal ice tongue of Kangiata Nunaata Sermia (KNS) at the head of Kangersuneq Fjord (KF), southwest Greenland. We calculate melt rates for March and May 2013 by differencing along-fjord surface elevation, derived from high-resolution TanDEM-X digital elevation models (DEMs), in combination with ice velocities derived from offset tracking applied to TerraSAR-X imagery. Estimated steady state melt rates reach up to 1.4 ± 0.5m d-1 near the glacier grounding line, with mean values of up to 0.8 ± 0.3 and 0.7 ± 0.3m d-1 for the eastern and western parts of the ice tongue, respectively. Melt rates decrease with distance from the ice front and vary across the fjord. This methodology reveals spatio-temporal variations in submarine melt rates (SMRs) at tidewater glaciers which develop floating termini, and can be used to improve our understanding of ice-ocean interactions and submarine melting in glacial fjords.Publisher PDFPeer reviewe

The coupling constant averaged exchange–correlation energy density

The exchange–correlation energy, central to density-functional theory, may be represented in terms of the coupling constant averaged (CCA) exchange–correlation energy density. We present an approach to calculate the CCA energy density using accurate ab initio methods and its application to simple atomic systems. This function provides a link between intrinsically non-local, many-body electronic structure methods and simple local and semi-local density-functional approximations (DFAs). The CCA energy density is resolved into separate exchange and correlation terms and the features of each compared with those of quantities commonly used to construct DFAs. In particular, the more complex structure of the correlation energy density is found to exhibit features that align well with those present in the Laplacian of the density, suggesting its role as a key variable to be used in the construction of improved semi-local correlation functionals. The accurate results presented in this work are also compared with those provided by the Laplacian-dependent Becke–Roussel model for the exchange energy

From Local Action to Global Policy: A Comparative Policy Content Analysis of National Policies to Address Musculoskeletal Health to Inform Global Policy Development

Background: Global policy to guide action on musculoskeletal (MSK) health is in a nascent phase. Lagging behind other non-communicable diseases (NCDs) there is currently little global policy to assist governments to develop national approaches to MSK health. Considering the importance of comparison and learning for global policy development, we aimed to perform a comparative analysis of national MSK policies to identify areas of innovation and draw common themes and principles that could guide MSK health policy. Methods: Multi-modal search strategy incorporating a systematic online search targeted at the 30 most populated nations; a call to networked experts; a specified question in a related eDelphi questionnaire; and snowballing methods. Extracted data were organised using an a priori framework adapted from the World Health Organization (WHO) Building Blocks and further inductive coding. Subsequently, texts were open coded and thematically analysed to derive specific sub-themes and principles underlying texts within each theme, serving as abstracted, transferable concepts for future global policy. Results: The search yielded 165 documents with 41 retained after removal of duplicates and exclusions. Only three documents were comprehensive national strategies addressing MSK health. The most common conditions addressed in the documents were pain (non-cancer), low back pain, occupational health, inflammatory conditions, and osteoarthritis. Across eight categories, we derived 47 sub-themes with transferable principles that could guide global policy for: service delivery; workforce; medicines and technologies; financing; data and information systems; leadership and governance; citizens, consumers and communities; and research and innovation. Conclusion: There are few examples of national strategic policy to address MSK health; however, many countries are moving towards this by documenting the burden of disease and developing policies for MSK services. This review found a breadth of principles that can add to this existing work and may be adopted to develop comprehensive system-wide MSK health approaches at national and global levels