Ariadne: synthetic long read deconvolution using assembly graphs.

Synthetic long read sequencing techniques such as UST's TELL-Seq and Loop Genomics' LoopSeq combine 3[Formula: see text] barcoding with standard short-read sequencing to expand the range of linkage resolution from hundreds to tens of thousands of base-pairs. However, the lack of a 1:1 correspondence between a long fragment and a 3[Formula: see text] unique molecular identifier confounds the assignment of linkage between short reads. We introduce Ariadne, a novel assembly graph-based synthetic long read deconvolution algorithm, that can be used to extract single-species read-clouds from synthetic long read datasets to improve the taxonomic classification and de novo assembly of complex populations, such as metagenomes.

A modular metagenomics analysis system for integrated multi-step data exploration.

Motivation: Computational analysis of large-scale metagenomics sequencing datasets has proved to be both incredibly valuable for extracting isolate-level taxonomic and functional insights from complex microbial communities. However, thanks to an ever-expanding ecosystem of metagenomics-specific algorithms and file formats, designing studies, implementing seamless and scalable end-to-end workflows, and exploring the massive amounts of output data have become studies unto themselves. Furthermore, there is little inter-communication between output data of different analytic purposes, such as short-read classification and metagenome assembled genomes (MAG) reconstruction. One-click pipelines have helped to organize these tools into targeted workflows, but they suffer from general compatibility and maintainability issues. Results: To address the gap in easily extensible yet robustly distributable metagenomics workflows, we have developed a module-based metagenomics analysis system written in Snakemake, a popular workflow management system, along with a standardized module and working directory architecture. Each module can be run independently or conjointly with a series of others to produce the target data format (ex. short-read preprocessing alone, or short-read preprocessing followed by de novo assembly), and outputs aggregated summary statistics reports and semi-guided Jupyter notebook-based visualizations, The module system is a bioinformatics-optimzied scaffold designed to be rapidly iterated upon by the research community at large. Availability: The module template as well as the modules described below can be found at https://github.com/MetaSUB-CAMP.

Gender-Inclusive Fellowship Naming and Equity, Diversity, and Inclusion in Radiology: An Analysis of Radiology Department Websites in Canada and the United States.

Purpose: Transgender and gender non-binary (TGNB) individuals face numerous inequalities in healthcare and there is substantial work to be done in fostering TGNB culturally competent care in radiology. A radiology department's online presence and use of gender-inclusive language are essential in promoting an environment of equity, diversity, and inclusion (EDI). The naming of radiology fellowships and continuing medical education (CME) courses with terminology such as "Women's Imaging" indicates a lack of inclusivity to TGNB patients and providers, which could result in suboptimal patient care. Methods: We conducted a cross-sectional analysis of all institutions in Canada and the United States (US) offering training in Breast Imaging, Women's Imaging, or Breast and Body Imaging. Data was collected from each institution's radiology department website pertaining to fellowship names, EDI involvement, and CME courses. Results: 8 Canadian and 71 US radiology fellowships were identified. 75% of Canadian and 90% of US fellowships had gender-inclusive names. One (12.5%) Canadian and 29 (41%) US institutions had EDI Committees mentioned on their websites. Among institutions publicly displaying CME courses about breast/body or women's imaging, gender-inclusive names were used in only 1 (25%) of the Canadian CME courses, compared to 81% of the US institutions. Conclusions: Most institutions in Canada and the US have gender-inclusive names for their radiology fellowships pertaining to breast and body imaging. However, there is much opportunity to and arguably the responsibility for institutions in both countries to increase the impact and visibility of their EDI efforts through creation of department-specific committees and CME courses.

A global metagenomic map of urban microbiomes and antimicrobial resistance.

We present a global atlas of 4,728 metagenomic samples from mass-transit systems in 60 cities over 3 years, representing the first systematic, worldwide catalog of the urban microbial ecosystem. This atlas provides an annotated, geospatial profile of microbial strains, functional characteristics, antimicrobial resistance (AMR) markers, and genetic elements, including 10,928 viruses, 1,302 bacteria, 2 archaea, and 838,532 CRISPR arrays not found in reference databases. We identified 4,246 known species of urban microorganisms and a consistent set of 31 species found in 97% of samples that were distinct from human commensal organisms. Profiles of AMR genes varied widely in type and density across cities. Cities showed distinct microbial taxonomic signatures that were driven by climate and geographic differences. These results constitute a high-resolution global metagenomic atlas that enables discovery of organisms and genes, highlights potential public health and forensic applications, and provides a culture-independent view of AMR burden in cities.

Reconstruction of Microbial Haplotypes by Integration of Statistical and Physical Linkage in Scaffolding.

DNA sequencing technologies provide unprecedented opportunities to analyze within-host evolution of microorganism populations. Often, within-host populations are analyzed via pooled sequencing of the population, which contains multiple individuals or "haplotypes." However, current next-generation sequencing instruments, in conjunction with single-molecule barcoded linked-reads, cannot distinguish long haplotypes directly. Computational reconstruction of haplotypes from pooled sequencing has been attempted in virology, bacterial genomics, metagenomics, and human genetics, using algorithms based on either cross-host genetic sharing or within-host genomic reads. Here, we describe PoolHapX, a flexible computational approach that integrates information from both genetic sharing and genomic sequencing. We demonstrated that PoolHapX outperforms state-of-the-art tools tailored to specific organismal systems, and is robust to within-host evolution. Importantly, together with barcoded linked-reads, PoolHapX can infer whole-chromosome-scale haplotypes from 50 pools each containing 12 different haplotypes. By analyzing real data, we uncovered dynamic variations in the evolutionary processes of within-patient HIV populations previously unobserved in single position-based analysis.

Evaluation of A Phylogenetic Pipeline to Examine Transmission Networks in A Canadian HIV Cohort.

Keywords: HIV; Canada; molecular phylogenetics; viral evolution; person-to-person transmission inference; transmission network; summary statistics.

The Integration of Clinical and Research Training: How and Why MD-PhD Programs Work.

For over 60 years, MD-PhD programs have provided integrated clinical and research training to produce graduates primed for physician-scientist careers. Yet the nature of this integrated training is poorly characterized, with no program theory of MD-PhD training to guide program development or evaluation. The authors address this gap by proposing a program theory of integrated MD-PhD training applying constructs from cognitive psychology and medical education. The authors argue that integrated physician-scientist training requires development of at least three elements in trainees: cognitive synergy, sense of self, and professional capacity. First, integrated programs need to foster the cognitive ability to synergize and transfer knowledge between the clinical and research realms. Second, integrated programs need to facilitate development of a unique and emergent identity as a physician-scientist that is more than the sum of the individual roles of physician and scientist. Third, integrated programs should develop core competencies unique to physician-scientists in addition to those required of each independently. The authors describe how programs can promote development of these elements in trainees, summarized in a logic model. Activities and process measures are provided to assist institutions in enhancing integration. Specifically, programs can enact the proposed theory by providing tailored MD-PhD curricula, personal development planning, and a supportive community of practice. It is high time to establish a theory behind integrated MD-PhD training as the basis for designing interventions and evaluations to develop the foundations of physician-scientist expertise.

PRESM: personalized reference editor for somatic mutation discovery in cancer genomics.

MOTIVATION: Accurate detection of somatic mutations is a crucial step toward understanding cancer. Various tools have been developed to detect somatic mutations from cancer genome sequencing data by mapping reads to a universal reference genome and inferring likelihoods from complex statistical models. However, read mapping is frequently obstructed by mismatches between germline and somatic mutations on a read and the reference genome. Previous attempts to develop personalized genome tools are not compatible with downstream statistical models for somatic mutation detection. RESULTS: We present PRESM, a tool that builds personalized reference genomes by integrating germline mutations into the reference genome. The aforementioned obstacle is circumvented by using a two-step germline substitution procedure, maintaining positional fidelity using an innovative workaround. Reads derived from tumor tissue can be positioned more accurately along a personalized reference than a universal reference due to the reduced genetic distance between the subject (tumor genome) and the target (the personalized genome). Application of PRESM's personalized genome reduced false-positive (FP) somatic mutation calls by as much as 55.5%, and facilitated the discovery of a novel somatic point mutation on a germline insertion in PDE1A, a phosphodiesterase associated with melanoma. Moreover, all improvements in calling accuracy were achieved without parameter optimization, as PRESM itself is parameter-free. Hence, similar increases in read mapping and decreases in the FP rate will persist when PRESM-built genomes are applied to any user-provided dataset. AVAILABILITY AND IMPLEMENTATION: The software is available at https://github.com/precisionomics/PRESM. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

SimPEL: Simulation-based power estimation for sequencing studies of low-prevalence conditions.

Power estimations are important for optimizing genotype-phenotype association study designs. However, existing frameworks are designed for common disorders, and thus ill-suited for the inherent challenges of studies for low-prevalence conditions such as rare diseases and infrequent adverse drug reactions. These challenges include small sample sizes and the need to leverage genetic annotation resources in association analyses for the purpose of ranking potential causal genes. We present SimPEL, a simulation-based program providing power estimations for the design of low-prevalence condition studies. SimPEL integrates the usage of gene annotation resources for association analyses. Customizable parameters, including the penetrance of the putative causal allele and the employed pathogenic scoring system, allow SimPEL to realistically model a large range of study designs. To demonstrate the effects of various parameters on power, we estimated the power of several simulated designs using SimPEL and captured power trends in agreement with observations from current literature on low-frequency condition studies. SimPEL, as a tool, provides researchers studying low-frequency conditions with an intuitive and highly flexible avenue for statistical power estimation. The platform-independent "batteries included" executable and default input files are available at https://github.com/precisionomics/SimPEL.

Resting-state functional connectivity in children born from gestations complicated by preeclampsia: A pilot study cohort.

BACKGROUND: Individuals (PE-F1s) born from preeclampsia (PE)-complicated pregnancies have elevated risks for cognitive impairment. Intervals of disturbed maternal plasma angiokines precede clinical signs of PE. We hypothesized pan-blastocyst dysregulation of angiokines underlies altered PE-F1 brain vascular and neurological development. This could alter brain functional connectivity (FC) patterns at rest. MATERIALS AND METHODS: Resting-state functional MRI datasets of ten, matched child pairs (5 boys and 5 girls aged 7-10 years of age) from PE or control pregnancies were available for study. Seed-based analysis and independent component analysis (ICA) methodologies were used to assess whether differences in resting-state functional connectivity (rs-FC) were present between PE-F1s and controls. Bilateral amygdala, bilateral hippocampus, and medial prefrontal cortex (MPFC) were selected as regions of interest (ROI) for the seed-based analysis based on previous imaging differences that we reported in this set of children. RESULTS: Compared to controls, PE-F1 children had increased rs-FC between the right amygdala and left frontal pole, the left amygdala and bilateral frontal pole, and the MPFC and precuneus. PE-F1 children additionally had decreased rs-FC between the MPFC and the left occipital fusiform gyrus compared to controls. CONCLUSION: These are the first reported rs-FC data for PE-F1s of any age. Theysuggest that PE alters FC during human fetal brain development. Altered FC may contribute to the behavioural and neurological alterations reported in PE-F1s. Longitudinal MRI studies with larger sample sizes are required to confirm these novel findings.

Neurological function in children born to preeclamptic and hypertensive mothers - A systematic review.

BACKGROUND: Offspring whose mothers developed preeclampsia (PE-F1s) show developmental effects that are now being identified, such as cognitive, behavioural, and mood differences compared to offspring from non-complicated pregnancies. We hypothesize that the progressive angiokine dysregulation associated with development of preeclampsia (PE) reflects gene dysregulation in pre-implantation conceptuses, and manifests in all developing fetal tissues rather than exclusively to the placenta. This hypothesis predicts that fetal cerebrovascular and brain development are deviated by fetal-intrinsic, brain-based mechanisms during what is currently considered a placentally-induced maternal disease. Due to our initial results from brain-imaging and cognitive screening in a child pilot PE-F1 cohort, we developed this systematic review to answer the question of whether any consistent neurological measurements have been found to discriminate between brain functions in offspring of mothers who experienced a hypertensive pregnancy vs. offspring of mothers that did not. METHODS: Relevant studies were searched systematically up to June 2017 in MEDLINE, PsycINFO, EMBASE and the grey literature. RESULTS: Following predetermined inclusion and exclusion criteria, our search identified 27 out of 464 studies reporting on neurological function in offspring born to preeclamptic and hypertensive mothers. CONCLUSION: The current literature strongly supports the conclusion of the behavioural and cognitive deviations in PE-F1s. However, only three studies associated their findings with brain measurements via magnetic resonance imaging (MRI) in both healthy and at-risk pediatric populations. PE-F1s should be identified as an at-risk pediatric population during brain development and studied further as a defined group, perhaps stratified by maternal plasma angiokine levels.

The Default Mode Network in Healthy Individuals: A Systematic Review and Meta-Analysis.

When the brain is not engaged in goal-directed activities and at rest, there are still measureable patterns of activity. One resting-state network, the default mode network (DMN) is responsible for a self-referential introspective state. There are many factors that influence normal changes in brain activity. The purpose of this review is to summarize differences in DMN functional connectivity in healthy individuals by age, sex, cognitive function, and analysis type to characterize what is "normal." Studies were systematically selected up to August 2016. Two reviewers independently used predetermined inclusion and exclusion criteria to identify relevant studies. Studies that provided sufficient information were included in a subsequent voxel-wise meta-analysis. Strength of DMN functional connectivity follows an inverse U-shape, where it is strongest in adulthood and lowest in children and elderly. Cognitive function is positively correlated with DMN functional connectivity. Females exhibit stronger intranetwork connectivity compared with males. Effects of analysis type were inconclusive and more studies need to incorporate complementing techniques. The voxel-wise meta-analysis was only conducted for the age factor. Findings supported an immature network in children compared with adults and a stronger network in adults compared with elderly. This is the first study to review differences of DMN functional connectivity in healthy individuals by age, sex, cognitive function, and analysis type. Findings add to the understanding of normal variance. Furthermore, defining a normal comparative base may allow for the identification of DMN change into pathology. This is important since it may allow for the detection of an intermediate risk phenotype and could serve as a biomarker for treatment response.

MD/PhD Training in Canada: Results from a national trainee and program director review.

PURPOSE: There has been limited examination of clinician scientist training in Canada, particularly regarding training integration and funding. This study assessed program structure, funding, tuition and mentorship structures available at Canadian MD/PhD programs. METHODS: Clinician Investigator Trainee Association of Canada administered an anonymous survey to current trainees and program directors that captured program structure, trainee funding, tuition and mentorship opportunities and needs across institutions. RESULTS: In June 2015, 101/228 (44%) trainees and 9/13 (69%) program directors completed the online survey. In all programs, students completed the PhD degree prior to clerkship training. Seven programs offered research training upon completion of pre-clerkship, four offered concurrent clinical and research training, and three offered alternative structures. Nine held seminars exposing students to clinical and research integration and two offered clinician scientist skills courses. Stipend funding and tuition varied, especially during clinical training years. Regarding mentorship, all programs held regular meetings, though eight programs do not have formal mentorship opportunities. Both trainees and program directors identified the need for further career planning and development support as a student priority. CONCLUSION: MD/PhD programs varied by program structure, funding, tuition and mentorship opportunities. Mechanisms to share and spread program innovations should be instated. Students may benefit from concurrent research and clinical training as well as courses specific to clinician scientist skill development. Decreasing debt burden may attract and retain trainees in this demanding path. To ensure mentorship programs align with trainee priorities, program directors should directly collaborate with students in their development and evaluation.

Is serotonin transporter polymorphism (5-HTTLPR) allele status a predictor for obsessive-compulsive disorder? A meta-analysis.

The serotonin transporter polymorphism has been implicated in obsessive-compulsive disorder (OCD). However, molecular genetic association studies have yielded inconsistent results. Variation may be due to lack of OCD subtype classification. The goal of this systematic review is to investigate the association of the S-allele of the serotonin transporter polymorphism with OCD and OCD subtypes. A total of 69 studies were initially found through a systematic search of the literature but only 13 with sufficient information to compute odds ratios were suitable for review. A total of 1991 participants with OCD and their 5-HTTLPR allele status were examined. The primary outcome measures were allele frequency and OCD diagnosis. A full meta-analysis was completed comparing the L- and S-alleles using a random effects model in RevMan 5.2.1. Further, a secondary meta-analysis stratified by sex and late-onset was conducted for S- versus L-allele frequency. In the primary meta-analysis, OCD was not associated with the S-allele of the 5-HTTLPR polymorphism (Z = 0.07, p = 0.94). Moreover, late-onset OCD was not associated with the S-allele (Z = 1.45, p = 0.15). However, when stratified by sex, there is an emerging sex-specific relationship. There was a trending association between the S-allele and OCD status in females (Z = 1.62, p = 0.10) but not in males (Z = 0.69, p = 0.49). The findings provide further support for the need of subtype classification of this heterogeneous disorder. Future studies should clearly examine sex differences and OCD age-of-onset. In particular, emphasis should be placed on the effect of female reproductive milestones on OCD onset and symptom exacerbation.