PanomiR: a systems biology framework for analysis of multi-pathway targeting by miRNAs.

Charting microRNA (miRNA) regulation across pathways is key to characterizing their function. Yet, no method currently exists that can quantify how miRNAs regulate multiple interconnected pathways or prioritize them for their ability to regulate coordinate transcriptional programs. Existing methods primarily infer one-to-one relationships between miRNAs and pathways using differentially expressed genes. We introduce PanomiR, an in silico framework for studying the interplay of miRNAs and disease functions. PanomiR integrates gene expression, mRNA-miRNA interactions and known biological pathways to reveal coordinated multi-pathway targeting by miRNAs. PanomiR utilizes pathway-activity profiling approaches, a pathway co-expression network and network clustering algorithms to prioritize miRNAs that target broad-scale transcriptional disease phenotypes. It directly resolves differential regulation of pathways, irrespective of their differential gene expression, and captures co-activity to establish functional pathway groupings and the miRNAs that may regulate them. PanomiR uses a systems biology approach to provide broad but precise insights into miRNA-regulated functional programs. It is available at https://bioconductor.org/packages/PanomiR.

Correction: Ten simple rules for leveraging virtual interaction to build higher-level learning into bioinformatics short courses.

[This corrects the article DOI: 10.1371/journal.pcbi.1010220.].

Clinical Use of Trabecular Bone Score: The 2023 ISCD Official Positions.

Osteoporosis can currently be diagnosed by applying the WHO classification to bone mineral density (BMD) assessed by dual-energy x-ray absorptiometry (DXA). However, skeletal factors other than BMD contribute to bone strength and fracture risk. Lumbar spine TBS, a grey-level texture measure which is derived from DXA images has been extensively studied, enhances fracture prediction independent of BMD and can be used to adjust fracture probability from FRAX® to improve risk stratification. The purpose of this International Society for Clinical Densitometry task force was to review the existing evidence and develop recommendations to assist clinicians regarding when and how to perform, report and utilize TBS. Our review concluded that TBS is most likely to alter clinical management in patients aged ≥ 40 years who are close to the pharmacologic intervention threshold by FRAX. The TBS value from L1-L4 vertebral levels, without vertebral exclusions, should be used to calculate adjusted FRAX probabilities. L1-L4 vertebral levels can be used in the presence of degenerative changes and lumbar compression fractures. It is recommended not to report TBS if extreme structural or pathological artifacts are present. Monitoring and reporting TBS change is unlikely to be helpful with the current version of the TBS algorithm. The next version of TBS software will include an adjustment based upon directly measured tissue thickness. This is expected to improve performance and address some of the technical factors that affect the current algorithm which may require modifications to these Official Positions as experience is acquired with this new algorithm.

Correction: Ten simple rules for organizing a bioinformatics training course in low- and middle-income countries.

[This corrects the article DOI: 10.1371/journal.pcbi.1009218.].

A new pan-European Train-the-Trainer programme for bioinformatics: pilot results on feasibility, utility and sustainability of learning.

Demand for training life scientists in bioinformatics methods, tools and resources and computational approaches is urgent and growing. To meet this demand, new trainers must be prepared with effective teaching practices for delivering short hands-on training sessions-a specific type of education that is not typically part of professional preparation of life scientists in many countries. A new Train-the-Trainer (TtT) programme was created by adapting existing models, using input from experienced trainers and experts in bioinformatics, and from educational and cognitive sciences. This programme was piloted across Europe from May 2016 to January 2017. Preparation included drafting the training materials, organizing sessions to pilot them and studying this paradigm for its potential to support the development and delivery of future bioinformatics training by participants. Seven pilot TtT sessions were carried out, and this manuscript describes the results of the pilot year. Lessons learned include (i) support is required for logistics, so that new instructors can focus on their teaching; (ii) institutions must provide incentives to include training opportunities for those who want/need to become new or better instructors; (iii) formal evaluation of the TtT materials is now a priority; (iv) a strategy is needed to recruit, train and certify new instructor trainers (faculty); and (v) future evaluations must assess utility. Additionally, defining a flexible but rigorous and reliable process of TtT 'certification' may incentivize participants and will be considered in future.

Ten simple rules for making training materials FAIR.

Everything we do today is becoming more and more reliant on the use of computers. The field of biology is no exception; but most biologists receive little or no formal preparation for the increasingly computational aspects of their discipline. In consequence, informal training courses are often needed to plug the gaps; and the demand for such training is growing worldwide. To meet this demand, some training programs are being expanded, and new ones are being developed. Key to both scenarios is the creation of new course materials. Rather than starting from scratch, however, it's sometimes possible to repurpose materials that already exist. Yet finding suitable materials online can be difficult: They're often widely scattered across the internet or hidden in their home institutions, with no systematic way to find them. This is a common problem for all digital objects. The scientific community has attempted to address this issue by developing a set of rules (which have been called the Findable, Accessible, Interoperable and Reusable [FAIR] principles) to make such objects more findable and reusable. Here, we show how to apply these rules to help make training materials easier to find, (re)use, and adapt, for the benefit of all.

A framework to assess the quality and impact of bioinformatics training across ELIXIR.

ELIXIR is a pan-European intergovernmental organisation for life science that aims to coordinate bioinformatics resources in a single infrastructure across Europe; bioinformatics training is central to its strategy, which aims to develop a training community that spans all ELIXIR member states. In an evidence-based approach for strengthening bioinformatics training programmes across Europe, the ELIXIR Training Platform, led by the ELIXIR EXCELERATE Quality and Impact Assessment Subtask in collaboration with the ELIXIR Training Coordinators Group, has implemented an assessment strategy to measure quality and impact of its entire training portfolio. Here, we present ELIXIR's framework for assessing training quality and impact, which includes the following: specifying assessment aims, determining what data to collect in order to address these aims, and our strategy for centralised data collection to allow for ELIXIR-wide analyses. In addition, we present an overview of the ELIXIR training data collected over the past 4 years. We highlight the importance of a coordinated and consistent data collection approach and the relevance of defining specific metrics and answer scales for consortium-wide analyses as well as for comparison of data across iterations of the same course.

Whole-genome sequencing reveals new Alzheimer's disease-associated rare variants in loci related to synaptic function and neuronal development.

INTRODUCTION: Genome-wide association studies have led to numerous genetic loci associated with Alzheimer's disease (AD). Whole-genome sequencing (WGS) now permits genome-wide analyses to identify rare variants contributing to AD risk. METHODS: We performed single-variant and spatial clustering-based testing on rare variants (minor allele frequency [MAF] ≤1%) in a family-based WGS-based association study of 2247 subjects from 605 multiplex AD families, followed by replication in 1669 unrelated individuals. RESULTS: We identified 13 new AD candidate loci that yielded consistent rare-variant signals in discovery and replication cohorts (4 from single-variant, 9 from spatial-clustering), implicating these genes: FNBP1L, SEL1L, LINC00298, PRKCH, C15ORF41, C2CD3, KIF2A, APC, LHX9, NALCN, CTNNA2, SYTL3, and CLSTN2. DISCUSSION: Downstream analyses of these novel loci highlight synaptic function, in contrast to common AD-associated variants, which implicate innate immunity and amyloid processing. These loci have not been associated previously with AD, emphasizing the ability of WGS to identify AD-associated rare variants, particularly outside of the exome.

Bone Mineral Densitometry Reporting: Pearls and Pitfalls.

Dual-energy X-ray absorptiometry (DXA) is the method of choice for assessing bone mineral density (BMD). Unfortunately, the performance and interpretation of DXA can be challenging and errors are common. In fact, it has been reported that up to 90% of BMD reports contain at least 1 error. Errors can be the result of technique or interpretative in nature or both and can result in inappropriate diagnosis and management. In this article, we review the various types of pitfalls frequently encountered by physicians interpreting DXA studies. Being aware of these pitfalls will help readers recognize and avoid them when encountered in clinical practice.

From trainees to trainers to instructors: Sustainably building a national capacity in bioinformatics training.

Demand for training life scientists in bioinformatics skills led to the development of a train-the-trainer collaboration between the European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI) and 2 Australian organisations, Bioplatforms Australia and Commonwealth Scientific and Industrial Research Organisation (CSIRO) in 2012. The goal of the collaboration was to establish a group of trained instructors who could develop and deliver short bioinformatics courses nationally. A train-the-trainer course introduces instructors to aspects of andragogy and evidence-based learning principles to help them better design, develop, and deliver high-quality training. Since then, both the number of trainers in the network and the course portfolio have grown. Best practises have been developed and shared between the Australian cohort and EMBL-EBI to address common challenges in bioinformatics training. The Australian trainer cohort undertook a train-the-trainer instructor course, again with EMBL-EBI, and subsequently successfully delivered train-the-trainer courses to interested bioinformatics trainers within Australia. We conclude that a train-the-trainer approach can help build national capacity and maintain a critical mass of trained instructors.

Pelvic floor disorder symptoms and bone strength in postmenopausal women.

INTRODUCTION AND HYPOTHESIS: The current study is aimed at characterizing the association between pelvic floor disorder symptoms and bone strength reflecting a potential connective tissue pathophysiology in postmenopausal women. METHODS: A cross-sectional study was conducted in postmenopausal women undergoing osteoporosis evaluation from 2007 to 2010. Urinary incontinence (UI) was defined as urinary leakage ≥2-3 times/week. UI types were defined using the 3 Incontinence Questionnaire. Fecal incontinence was defined as stool leakage ≥1/month, and pelvic organ prolapse as a positive response to "Do you have a bulge or something falling out that you can see or feel in your vaginal area?" Bone quality and quantity were assessed using the trabecular bone score (TBS) and bone mineral density respectively: bone strength was defined by combined quality/quantity index, low strength being equivalent to moderate to severe fracture risk; low quality as TBS ≤ 1.31; low quantity by T-score <-1 or on osteoporosis medication. RESULTS: Of 681 subjects, 262 had low bone strength whereas 419 were normal using the combined quality/quantity bone assessment. Characteristics were similar except for age (low bone strength: 69.0 ± 8.2 vs normal: 65.0 ± 7.1, p < 0.01) and smoking (8.8% vs 3.3%, p < 0.01). Low bone strength was associated with any UI (adjusted odds ratio [aOR]: 1.48, 1.05-2.10), stress (aOR: 1.53, 1.06-2.21), and mixed (aOR :1.45, 1.02-2.05). Women with low bone quality had increased odds of UI (any, urgency, mixed), whereas none of the pelvic floor disorder symptoms was associated with low bone quantity. CONCLUSIONS: Low bone strength defined by a combined quantity/quality index, as well as low bone quality alone, were associated with increased risk of UI.

The development and application of bioinformatics core competencies to improve bioinformatics training and education.

Bioinformatics is recognized as part of the essential knowledge base of numerous career paths in biomedical research and healthcare. However, there is little agreement in the field over what that knowledge entails or how best to provide it. These disagreements are compounded by the wide range of populations in need of bioinformatics training, with divergent prior backgrounds and intended application areas. The Curriculum Task Force of the International Society of Computational Biology (ISCB) Education Committee has sought to provide a framework for training needs and curricula in terms of a set of bioinformatics core competencies that cut across many user personas and training programs. The initial competencies developed based on surveys of employers and training programs have since been refined through a multiyear process of community engagement. This report describes the current status of the competencies and presents a series of use cases illustrating how they are being applied in diverse training contexts. These use cases are intended to demonstrate how others can make use of the competencies and engage in the process of their continuing refinement and application. The report concludes with a consideration of remaining challenges and future plans.

Use of Bone Health Evaluation in Orthopedic Surgery: 2019 ISCD Official Position.

This position development conference (PDC) Task Force examined the assessment of bone status in orthopedic surgery patients. Key questions included which orthopedic surgery patients should be evaluated for poor bone health prior to surgery and which subsets of patients are at high risk for poor bone health and adverse outcomes. Second, the reliability and validity of using bone densitometry techniques and measurement of specific geometries around the hip and knee before and after arthroplasty was determined. Finally, the use of computed tomography (CT) attenuation coefficients (Hounsfield units) to estimate bone quality at anatomic locations where orthopedic surgery is performed including femur, tibia, shoulder, wrist, and ankle were reviewed. The literature review identified 665 articles of which 198 met inclusion exclusion criteria and were selected based on reporting of methodology, reliability, or validity results. We recommend that the orthopedic surgeon be aware of established ISCD guidelines for determining who should have additional screening for osteoporosis. Patients with inflammatory arthritis, chronic corticosteroid use, chronic renal disease, and those with history of fracture after age 50 are at high risk of osteoporosis and adverse events from surgery and should have dual energy X-ray absorptiometry (DXA) screening before surgery. In addition to standard DXA, bone mineral density (BMD) measurement along the femur and proximal tibia is reliable and valid around implants and can provide valuable information regarding bone remodeling and identification of loosening. Attention to positioning, selection of regions of interest, and use of special techniques and software is required. Plain radiographs and CT provide simple, reliable methods to classify the shape of the proximal femur and to predict osteoporosis; these include the Dorr Classification, Cortical Index, and critical thickness. Correlation of these indices to central BMD is moderate to good. Many patients undergoing orthopedic surgery have had preoperative CT which can be utilized to assess regional quality of bone. The simplest method available on most picture archiving and communications systems is to simply measure a regions of interest and determine the mean Hounsfield units. This method has excellent reliability throughout the skeleton and has moderate correlation to DXA based on BMD. The prediction of outcome and correlation to mechanical strength of fixation of a screw or implant is unknown.

Case-Based Review of Osteonecrosis of the Jaw (ONJ) and Application of the International Recommendations for Management From the International Task Force on ONJ.

Osteonecrosis of the jaw (ONJ) has been associated with antiresorptive therapy in both oncology and osteoporosis patients. This debilitating condition is very rare and advances in diagnosis and management may now effectively reduce the risk of its development and offer valuable treatment options for affected patients. This paper provides a case-based review of ONJ and application of the International Task Force on ONJ (referred to as the "Task Force") recommendations for the diagnosis and management of ONJ. The Task Force was supported by 14 international societies and achieved consensus from representatives of these multidisciplinary societies on key issues pertaining to the diagnosis and management of ONJ. The frequency of ONJ in oncology patients receiving oncology doses of bisphosphonate (BP) or denosumab is estimated at 1%-15%, and the frequency in the osteoporosis patient population receiving much lower doses of BP or denosumab is estimated at 0.001%-0.01%. Although the diagnosis of ONJ is primarily clinical, imaging may be helpful in confirming the diagnosis and staging. In those with multiple risk factors for ONJ for whom major invasive oral surgery is being planned, interruption of BP or denosumab therapy (in cancer patients) is advised, if possible, before surgery, until the surgical site heals. Major oral surgery in this context could include multiple extractions if surgical extractions are required, not simple forceps extractions. ONJ development may be reduced by optimizing oral hygiene and postoperatively using topical and systemic antibiotics as appropriate. Periodontal disease should be managed before starting oncology doses of BP or denosumab. Local debridement may be successful in disease unresponsive to conservative therapy. Successful surgical intervention has been reported in those with stage 3 disease; less severe disease is best managed conservatively. Teriparatide may be helpful in healing ONJ lesions and may be considered in osteoporosis patients at a high fracture risk in the absence of contraindications. Resumption of BP or denosumab therapy following healing of ONJ lesions is recommended, and there have not been reports of subsequent local recurrence.

Best Practices for Dual-Energy X-ray Absorptiometry Measurement and Reporting: International Society for Clinical Densitometry Guidance.

Dual-energy X-ray absorptiometry (DXA) is a technology that is widely used to diagnose osteoporosis, assess fracture risk, and monitor changes in bone mineral density (BMD). The clinical utility of DXA is highly dependent on the quality of the scan acquisition, analysis, and interpretation. Clinicians are best equipped to manage patients when BMD measurements are correct and interpretation follows well-established standards. Poor-quality acquisition, analysis, or interpretation of DXA data may mislead referring clinicians, resulting in unnecessary diagnostic evaluations, failure to evaluate when needed, inappropriate treatment, or failure to provide medical treatment, with potentially ineffective, harmful, or costly consequences. Misallocation of limited healthcare resources and poor treatment decisions can be minimized, and patient care optimized, through meticulous attention to DXA instrument calibration, data acquisition and analysis, interpretation, and reporting. This document from the International Society for Clinical Densitometry describes quality standards for BMD testing at DXA facilities worldwide to provide guidance for DXA supervisors, technologists, interpreters, and clinicians. High-quality DXA testing is necessary for correct diagnostic classification and optimal fracture risk assessment, and is essential for BMD monitoring.

The effect of extending femur scan length on BMD results on the Hologic Discovery-W scanner.

A longer dual-energy X-ray absorptiometry scan field of the hip may be useful for the detection of atypical subtrochanteric femur fractures. It has been demonstrated in a Prodigy GE/Lunar scanner that extending the scan length does not affect bone mineral density (BMD) results at the total hip or femoral neck. We hypothesized that extending the scan field on a Hologic Discovery scanner would also have no effect on BMD results at the hip. Thirty subjects who presented for standard of care dual-energy X-ray absorptiometry scans underwent paired default (15.2 cm) and extended (24.1 cm) length hip scans. There was no significant difference in the total hip or any of the component subregions of femoral neck, greater trochanter, or intertrochanteric (shaft) BMD between the default and extended length scans.