The Monarch Initiative in 2024: an analytic platform integrating phenotypes, genes and diseases across species.

Bridging the gap between genetic variations, environmental determinants, and phenotypic outcomes is critical for supporting clinical diagnosis and understanding mechanisms of diseases. It requires integrating open data at a global scale. The Monarch Initiative advances these goals by developing open ontologies, semantic data models, and knowledge graphs for translational research. The Monarch App is an integrated platform combining data about genes, phenotypes, and diseases across species. Monarch's APIs enable access to carefully curated datasets and advanced analysis tools that support the understanding and diagnosis of disease for diverse applications such as variant prioritization, deep phenotyping, and patient profile-matching. We have migrated our system into a scalable, cloud-based infrastructure; simplified Monarch's data ingestion and knowledge graph integration systems; enhanced data mapping and integration standards; and developed a new user interface with novel search and graph navigation features. Furthermore, we advanced Monarch's analytic tools by developing a customized plugin for OpenAI's ChatGPT to increase the reliability of its responses about phenotypic data, allowing us to interrogate the knowledge in the Monarch graph using state-of-the-art Large Language Models. The resources of the Monarch Initiative can be found at monarchinitiative.org and its corresponding code repository at github.com/monarch-initiative/monarch-app.

Hippocampal Neuroimaging-Informed Clinical Trial Enrichment Tool for Amnestic Mild Cognitive Impairment Using Open Data.

Our goal was to assess the enrichment utility of hippocampal volume (HV) as an enrichment biomarker in amnestic mild cognitive impairment (aMCI) clinical trials, and, hence, develop an HV neuroimaging-informed clinical trial enrichment tool. Modeling of integrated longitudinal patient-level data came from open-access natural history studies in patients diagnosed with aMCI-the Alzheimer's Disease Neuroimaging Initiative (ADNI)-1 and ADNI-2-and indicated that a decrease of 1 cm3 with respect to the analysis dataset median baseline intracranial volume-adjusted HV (ICV-HV; ~ 5 cm3 ) is associated with > 50% increase in disease progression rate as measured by the Clinical Dementia Rating Scale-Sum of Boxes. Clinical trial simulations showed that the inclusion of aMCI subjects with baseline ICV-HV below the 84th or 50th percentile allowed an approximate reduction in trial size of at least 26% and 55%, respectively. This clinical trial enrichment tool can help design more efficient and informative clinical trials.

The MSOAC approach to developing performance outcomes to measure and monitor multiple sclerosis disability.

BACKGROUND: The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) was formed by the National MS Society to develop improved measures of multiple sclerosis (MS)-related disability. OBJECTIVES: (1) To assess the current literature and available data on functional performance outcome measures (PerfOs) and (2) to determine suitability of using PerfOs to quantify MS disability in MS clinical trials. METHODS: (1) Identify disability dimensions common in MS; (2) conduct a comprehensive literature review of measures for those dimensions; (3) develop an MS Clinical Data Interchange Standards Consortium (CDISC) data standard; (4) create a database of standardized, pooled clinical trial data; (5) analyze the pooled data to assess psychometric properties of candidate measures; and (6) work with regulatory agencies to use the measures as primary or secondary outcomes in MS clinical trials. CONCLUSION: Considerable data exist supporting measures of the functional domains ambulation, manual dexterity, vision, and cognition. A CDISC standard for MS ( http://www.cdisc.org/therapeutic#MS ) was published, allowing pooling of clinical trial data. MSOAC member organizations contributed clinical data from 16 trials, including 14,370 subjects. Data from placebo-arm subjects are available to qualified researchers. This integrated, standardized dataset is being analyzed to support qualification of disability endpoints by regulatory agencies.

Y-balance test performance and BMI are associated with ankle sprain injury in collegiate male athletes.

OBJECTIVES: To determine if static balance, dynamic balance, ankle range of motion, body mass index (BMI), or history of an ankle sprain were associated with ankle sprain injuries within male and female collegiate athletes. DESIGN: Prospective cohort. METHODS: Three hundred and eighty-four male (age=19.79±1.80 years, height=178.02±10.39cm, mass=85.71±17.59kg) and one hundred and sixty seven female (age=19.80±1.52 years, height=165.61±7.08cm, mass=66.16±10.53kg) collegiate athletes involved in a variety of sports at a NCAA Division II or NAIA institution participated. Baseline measures of the Y-Balance (YBT), modified Balance Error Scoring System (mBESS), weight-bearing lunge test (WBLT), BMI, and history of ankle sprain were recorded. Participants were followed prospectively for two years and incidence of ankle sprain injury was documented. The average of the WBLT, mBESS, and YBT measures were used for analysis. Male and female participants were analyzed separately. Mann-Whitney U tests were utilized to identify variables which may be significantly associated with ankle sprain injury for logistic regression analysis. RESULTS: A total of 59 (38 males and 21 females) individuals sustained an ankle sprain during the follow up period. The binary logistic regression revealed BMI (Nagelkerke R2=0.069; X2=12.89; p<0.001; OR=3.85; 95% CI, 1.90-7.79; p<0.001) and anterior reach of the YBT (Nagelkerke R2=0.074; X2=13.70, p<0.001; OR=3.64; 95% CI=1.83-7.23; p=0.01) were significantly associated with ankle sprain injury in male athletes. No variables were associated with ankle sprain injury within female athletes. CONCLUSIONS: Male collegiate athletes with greater BMI and lesser YBT anterior reach were at a greater risk of sustaining an ankle sprain injury.

Y-Balance Test Performance Following a Competitive Field Hockey Season: A Pretest-Posttest Study.

CONTEXT: The Y-Balance Test (YBT) is a dynamic balance assessment used as a preseason musculoskeletal screen to determine injury risk. While the YBT has demonstrated excellent test-retest reliability, it is unknown if YBT performance changes following participation in a competitive athletic season. OBJECTIVE: Determine if a competitive athletic season affects YBT performance in field hockey players. DESIGN: Pretest-posttest. SETTING: Laboratory. PARTICIPANTS: 20 NCAA Division I women's field hockey players (age = 19.55 ± 1.30 y; height = 165.10 ± 5.277 cm; mass = 62.62 ± 4.64 kg) from a single team volunteered. Participants had to be free from injury throughout the entire study and participate in all athletic activities. INTERVENTIONS: Participants completed data collection sessions prior to (preseason) and following the athletic season (postseason). Between data collections, participants competed in the fall competitive field hockey season, which was ~3 months in duration. During data collection, participants completed the YBT bilaterally. MAIN OUTCOME MEASURES: The independent variable was time (preseason, postseason) and the dependent variables were normalized reach distances (anterior, posteromedial, posterolateral, composite) and between-limb symmetry for each reach direction. Differences between preseason and postseason were examined using paired t tests (P ≤ .05) as well as Bland-Altman limits of agreement. RESULTS: 4 players sustained a lower extremity injury during the season and were excluded from analysis. There were no significant differences between preseason and postseason reach distances for any reach directions on either limb (P ≥ .31) or in the between-limb symmetries (P ≥ .52). The limits of agreement analyses determined there was a low mean bias across measurements (≤1.67%); however, the 95% confidence intervals indicated there was high variability within the posterior reach directions over time (±4.75 to ± 14.83%). CONCLUSION: No changes in YBT performance were identified following a competitive field hockey season in Division I female athletes. However, the variability within the posterior reach directions over time may contribute to the limited use of these directions for injury risk stratification.

Draft genome sequence of Microbacterium oleivorans strain Wellendorf implicates heterotrophic versatility and bioremediation potential.

Microbacterium oleivorans is a predominant member of hydrocarbon-contaminated environments. We here report on the genomic analysis of M. oleivorans strain Wellendorf that was isolated from an indoor door handle. The partial genome of M. oleivorans strain Wellendorf consists of 2,916,870 bp of DNA with 2831 protein-coding genes and 49 RNA genes. The organism appears to be a versatile mesophilic heterotroph potentially capable of hydrolysis a suite of carbohydrates and amino acids. Genomic analysis revealed metabolic versatility with genes involved in the metabolism and transport of glucose, fructose, rhamnose, galactose, xylose, arabinose, alanine, aspartate, asparagine, glutamate, serine, glycine, threonine and cysteine. This is the first detailed analysis of a Microbacterium oleivorans genome.

Reliability and responsiveness of gait initiation profiles in those with chronic ankle instability.

Individuals with chronic ankle instability (CAI) have demonstrated deviations in gait initiation (GI) compared to healthy individuals. However, the intersession reliability of GI measures remains unknown in this population. The objective of this study was to determine the reliability and responsiveness of GI measures between two testing days in those with CAI. Twelve individuals with CAI volunteered. Participants performed barefoot GI on a force plate which captured center of pressure (COP). Data was collected on two separate occasions separated by one week. The GI profile was separated into three phases (S1, S2, and S3). S1 began from the deviation of normal balanced standing to the most posterolateral displacement under the stepping limb. S2 began from the end of S1 to the maximum medial position under the stance foot. S3 began at the end of S2 and continued until the vertical ground reaction force dropped below 100N. COP displacement (cm) was calculated as the sum of resultant vectors of the medial-lateral and anterior-posterior excursions for adjacent COP data points within each phase. The averages of 5 trials were used for analyses. Intraclass correlation coefficients (ICC(2,5)), standard error of measurement, and minimum detectable change (MDC) were calculated to determine reliability and responsiveness. S1, S2, and S3 displacement values were highly reliable between days (ICC(2,5) ≥0.76) with the exception of anterior-posterior S1 and medial-lateral S3. MDC values were relatively small (0.6-2.2cm). GI can be reliably assessed in those with CAI which is important for identifying interventions to alter GI profiles in these individuals.

Various methods for assessing static lower extremity alignment: implications for prospective risk-factor screenings.

CONTEXT: Accurate, efficient, and reliable measurement methods are essential to prospectively identify risk factors for knee injuries in large cohorts. OBJECTIVE: To determine tester reliability using digital photographs for the measurement of static lower extremity alignment (LEA) and whether values quantified with an electromagnetic motion-tracking system are in agreement with those quantified with clinical methods and digital photographs. DESIGN: Descriptive laboratory study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Thirty-three individuals participated and included 17 (10 women, 7 men; age = 21.7 ± 2.7 years, height = 163.4 ± 6.4 cm, mass = 59.7 ± 7.8 kg, body mass index = 23.7 ± 2.6 kg/m2) in study 1, in which we examined the reliability between clinical measures and digital photographs in 1 trained and 1 novice investigator, and 16 (11 women, 5 men; age = 22.3 ± 1.6 years, height = 170.3 ± 6.9 cm, mass = 72.9 ± 16.4 kg, body mass index = 25.2 ± 5.4 kg/m2) in study 2, in which we examined the agreement among clinical measures, digital photographs, and an electromagnetic tracking system. INTERVENTION(S): We evaluated measures of pelvic angle, quadriceps angle, tibiofemoral angle, genu recurvatum, femur length, and tibia length. Clinical measures were assessed using clinically accepted methods. Frontal- and sagittal-plane digital images were captured and imported into a computer software program. Anatomic landmarks were digitized using an electromagnetic tracking system to calculate static LEA. MAIN OUTCOME MEASURE(S): Intraclass correlation coefficients and standard errors of measurement were calculated to examine tester reliability. We calculated 95% limits of agreement and used Bland-Altman plots to examine agreement among clinical measures, digital photographs, and an electromagnetic tracking system. RESULTS: Using digital photographs, fair to excellent intratester (intraclass correlation coefficient range = 0.70-0.99) and intertester (intraclass correlation coefficient range = 0.75-0.97) reliability were observed for static knee alignment and limb-length measures. An acceptable level of agreement was observed between clinical measures and digital pictures for limb-length measures. When comparing clinical measures and digital photographs with the electromagnetic tracking system, an acceptable level of agreement was observed in measures of static knee angles and limb-length measures. CONCLUSIONS: The use of digital photographs and an electromagnetic tracking system appears to be an efficient and reliable method to assess static knee alignment and limb-length measurements.