Genome-wide association analysis of composite sleep health scores in 413,904 individuals.

Recent genome-wide association studies (GWASs) of several individual sleep traits have identified hundreds of genetic loci, suggesting diverse mechanisms. Moreover, sleep traits are moderately correlated, and together may provide a more complete picture of sleep health, while also illuminating distinct domains. Here we construct novel sleep health scores (SHSs) incorporating five core self-report measures: sleep duration, insomnia symptoms, chronotype, snoring, and daytime sleepiness, using additive (SHS-ADD) and five principal components-based (SHS-PCs) approaches. GWASs of these six SHSs identify 28 significant novel loci adjusting for multiple testing on six traits (p<8.3e-9), along with 341 previously reported loci (p<5e-08). The heritability of the first three SHS-PCs equals or exceeds that of SHS-ADD (SNP-h2=0.094), while revealing sleep-domain-specific genetic discoveries. Significant loci enrich in multiple brain tissues and in metabolic and neuronal pathways. Post GWAS analyses uncover novel genetic mechanisms underlying sleep health and reveal connections to behavioral, psychological, and cardiometabolic traits.

Preeclampsia Prediction Using Machine Learning and Polygenic Risk Scores From Clinical and Genetic Risk Factors in Early and Late Pregnancies.

BACKGROUND: Preeclampsia, a pregnancy-specific condition associated with new-onset hypertension after 20-weeks gestation, is a leading cause of maternal and neonatal morbidity and mortality. Predictive tools to understand which individuals are most at risk are needed. METHODS: We identified a cohort of N=1125 pregnant individuals who delivered between May 2015 and May 2022 at Mass General Brigham Hospitals with available electronic health record data and linked genetic data. Using clinical electronic health record data and systolic blood pressure polygenic risk scores derived from a large genome-wide association study, we developed machine learning (XGBoost) and logistic regression models to predict preeclampsia risk. RESULTS: Pregnant individuals with a systolic blood pressure polygenic risk score in the top quartile had higher blood pressures throughout pregnancy compared with patients within the lowest quartile systolic blood pressure polygenic risk score. In the first trimester, the most predictive model was XGBoost, with an area under the curve of 0.74. In late pregnancy, with data obtained up to the delivery admission, the best-performing model was XGBoost using clinical variables, which achieved an area under the curve of 0.91. Adding the systolic blood pressure polygenic risk score to the models did not improve the performance significantly based on De Long test comparing the area under the curve of models with and without the polygenic score. CONCLUSIONS: Integrating clinical factors into predictive models can inform personalized preeclampsia risk and achieve higher predictive power than the current practice. In the future, personalized tools can be implemented to identify high-risk patients for preventative therapies and timely intervention to improve adverse maternal and neonatal outcomes.

Natural history of retinitis pigmentosa based on genotype, vitamin A/E supplementation, and an electroretinogram biomarker.

BACKGROUNDA randomized clinical trial from 1984 to 1992 indicated that vitamin A supplementation had a beneficial effect on the progression of retinitis pigmentosa (RP), while vitamin E had an adverse effect.METHODSSequencing of banked DNA samples from that trial provided the opportunity to determine whether certain genotypes responded preferentially to vitamin supplementation.RESULTSThe genetic solution rate was 587 out of 765 (77%) of sequenced samples. Combining genetic solutions with electroretinogram outcomes showed that there were systematic differences in severity and progression seen among different genetic subtypes of RP, extending findings made for USH2A, RHO, RPGR, PRPF31, and EYS. Baseline electroretinogram 30-Hz flicker implicit time was an independent, strong predictor of progression rate. Using additional data and baseline implicit time as a predictor, the deleterious effect of vitamin E was still present. Surprisingly, the effect of vitamin A progression in the cohort as a whole was not detectable, with or without data from subsequent trials. Subgroup analyses are also discussed.CONCLUSIONOverall, genetic subtype and implicit time have significant predictive power for a patient's rate of progression, which is useful prognostically. While vitamin E supplementation should still be avoided, these data do not support a generalized neuroprotective effect of vitamin A for all types of RP.TRIAL REGISTRATIONClinicalTrials.gov NCT00000114, NCT00000116, and NCT00346333.FUNDINGFoundation Fighting Blindness and the National Eye Institute: R01 EY012910, R01 EY031036, R01 EY026904, and P30 EY014104.

Prediction of Preeclampsia from Clinical and Genetic Risk Factors in Early and Late Pregnancy Using Machine Learning and Polygenic Risk Scores.

Background: Preeclampsia, a pregnancy-specific condition associated with new-onset hypertension after 20 weeks gestation, is a leading cause of maternal and neonatal morbidity and mortality. Predictive tools to understand which individuals are most at risk are needed. Methods: We identified a cohort of N=1,125 pregnant individuals who delivered between 05/2015-05/2022 at Mass General Brigham hospitals with available electronic health record (EHR) data and linked genetic data. Using clinical EHR data and systolic blood pressure polygenic risk scores (SBP PRS) derived from a large genome-wide association study, we developed machine learning (xgboost) and linear regression models to predict preeclampsia risk. Results: Pregnant individuals with an SBP PRS in the top quartile had higher blood pressures throughout pregnancy compared to patients within the lowest quartile SBP PRS. In the first trimester, the most predictive model was xgboost, with an area under the curve (AUC) of 0.73. Adding the SBP PRS to the models improved the performance only of the linear regression model from AUC 0.70 to 0.71; the predictive power of other models remained unchanged. In late pregnancy, with data obtained up to the delivery admission, the best performing model was xgboost using clinical variables, which achieved an AUC of 0.91. Conclusions: Integrating clinical and genetic factors into predictive models can inform personalized preeclampsia risk and achieve higher predictive power than the current practice. In the future, personalized tools can be implemented in clinical practice to identify high-risk patients for preventative therapies and timely intervention to improve adverse maternal and neonatal outcomes.

A ten-year retrospective case review of risk factors associated with sleep-related infant deaths.

AIM: The study aimed to identify risk factors associated with sleep-related deaths of infants (0-24 months) in the province of Manitoba, Canada, between January 2009 and December 2018. METHODS: A systematic retrospective case review of autopsies and administrative records in Manitoba between 2009 and 2018. RESULTS: A total of 145 infants died in cases where unsafe sleep environments were known to have contributed to or resulted in their death and where no explained medical causes were identified. Where data complete, all infants had at least one known risk factor for sleep-related deaths, and 96% had multiple. The most common risk factors increased over time and included objects in the sleeping environment (90% of cases), not approved sleep surfaces (77%) and bedsharing (50%). Indigenous infants, infants of young mothers and infants in low-income neighbourhoods are overrepresented. Risk factors for Indigenous infants differed from cases involving non-Indigenous infants. CONCLUSION: A high proportion of sleep-related infant deaths were associated with not approved sleep surfaces and bedsharing, especially for infants under one year. Families in low-income neighbourhoods, Indigenous families and families with young mothers were disproportionately affected by sleep-related infant deaths. There is a need to enhance messaging and smoking cessation messaging in Indigenous communities to prevent sleep-related deaths.

The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK).

PURPOSE: In Mendelian disease diagnosis, variant analysis is a repetitive, error-prone, and time consuming process. To address this, we have developed the Mendelian Analysis Toolkit (MATK), a configurable, automated variant ranking program. METHODS: MATK aggregates variant information from multiple annotation sources and uses expert-designed rules with parameterized weights to produce a ranked list of potentially causal solutions. MATK performance was measured by a comparison between MATK-aided and human-domain expert analyses of 1060 families with inherited retinal degeneration (IRD), analyzed using an IRD-specific gene panel (589 individuals) and exome sequencing (471 families). RESULTS: When comparing MATK-assisted analysis with expert curation in both the IRD-specific gene panel and exome sequencing (1060 subjects), 97.3% of potential solutions found by experts were also identified by the MATK-assisted analysis (541 solutions identified with MATK of 556 solutions found by conventional analysis). Furthermore, MATK-assisted analysis identified 114 additional potential solutions from the 504 cases unsolved by conventional analysis. CONCLUSION: MATK expedites the process of identification of likely solving variants in Mendelian traits, and reduces variability stemming from human error and researcher bias. MATK facilitates data reanalysis to keep up with the constantly improving annotation sources and next-generation sequencing processing pipelines. The software is open source and available at https://gitlab.com/matthew_maher/mendelanalysis.

Posteroanterior Cervical Transcutaneous Spinal Cord Stimulation: Interactions with Cortical and Peripheral Nerve Stimulation.

Transcutaneous spinal cord stimulation (TSCS) has demonstrated potential to beneficially modulate spinal cord motor and autonomic circuitry. We are interested in pairing cervical TSCS with other forms of nervous system stimulation to enhance synaptic plasticity in circuits serving hand function. We use a novel configuration for cervical TSCS in which the anode is placed anteriorly over ~C4-C5 and the cathode posteriorly over ~T2-T4. We measured the effects of single pulses of TSCS paired with single pulses of motor cortex or median nerve stimulation timed to arrive at the cervical spinal cord at varying intervals. In 13 participants with and 15 participants without chronic cervical spinal cord injury, we observed that subthreshold TSCS facilitates hand muscle responses to motor cortex stimulation, with a tendency toward greater facilitation when TSCS is timed to arrive at cervical synapses simultaneously or up to 10 milliseconds after cortical stimulus arrival. Single pulses of subthreshold TSCS had no effect on the amplitudes of median H-reflex responses or F-wave responses. These findings support a model in which TSCS paired with appropriately timed cortical stimulation has the potential to facilitate convergent transmission between descending motor circuits, segmental afferents, and spinal motor neurons serving the hand. Studies with larger numbers of participants and repetitively paired cortical and spinal stimulation are needed.

Heart rate and blood pressure response improve the prediction of orthostatic cardiovascular dysregulation in persons with chronic spinal cord injury.

Unstable blood pressure after spinal cord injury (SCI) is not routinely examined but rather predicted by level and completeness of injury (i.e., American Spinal Injury Association Impairment Scale AIS classification). Our aim was to investigate hemodynamic response to a sit-up test in a large cohort of individuals with chronic SCI to better understand cardiovascular function in this population. Continuous blood pressure and ECG were recorded from individuals with SCI (n = 159) and non-injured individuals (n = 48). We found orthostatic hypotension occurred within each level and AIS classification (n = 36). Moreover, 45 individuals with chronic SCI experienced a drop in blood pressure that did not meet the criteria for orthostatic hypotension, but was accompanied by dramatic increases in heart rate, reflecting orthostatic intolerance. A cluster analysis of hemodynamic response to a seated position identified eight distinct patterns of interaction between blood pressure and heart rate during orthostatic stress indicating varied autonomic responses. Algorithmic cluster analysis of heart rate and blood pressure is more sensitive to diagnosing orthostatic cardiovascular dysregulation. This indicates blood pressure instability cannot be predicted by level and completeness of SCI, and the consensus statement definition of orthostatic hypotension is insufficient to characterize the variability of blood pressure and heart rate responses during orthostatic stress. Both blood pressure and heart rate responses are needed to characterize autonomic function after SCI.

Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations.

PURPOSE: Current sequencing strategies can genetically solve 55-60% of inherited retinal degeneration (IRD) cases, despite recent progress in sequencing. This can partially be attributed to elusive pathogenic variants (PVs) in known IRD genes, including copy-number variations (CNVs), which have been shown as major contributors to unsolved IRD cases. METHODS: Five hundred IRD patients were analyzed with targeted next-generation sequencing (NGS). The NGS data were used to detect CNVs with ExomeDepth and gCNV and the results were compared with CNV detection with a single-nucleotide polymorphism (SNP) array. Likely causal CNV predictions were validated by quantitative polymerase chain reaction (qPCR). RESULTS: Likely disease-causing single-nucleotide variants (SNVs) and small indels were found in 55.6% of subjects. PVs in USH2A (11.6%), RPGR (4%), and EYS (4%) were the most common. Likely causal CNVs were found in an additional 8.8% of patients. Of the three CNV detection methods, gCNV showed the highest accuracy. Approximately 30% of unsolved subjects had a single likely PV in a recessive IRD gene. CONCLUSION: CNV detection using NGS-based algorithms is a reliable method that greatly increases the genetic diagnostic rate of IRDs. Experimentally validating CNVs helps estimate the rate at which IRDs might be solved by a CNV plus a more elusive variant.

Posteroanterior cervical transcutaneous spinal stimulation targets ventral and dorsal nerve roots.

OBJECTIVE: We aim to non-invasively facilitate activation of spared neural circuits after cervical spinal cord injury (SCI) and amyotrophic lateral sclerosis (ALS). We developed and tested a novel configuration for cervical transcutaneous spinal stimulation (cTSS). METHODS: cTSS was delivered via electrodes placed over the midline at ~T2-T4 levels posteriorly and ~C4-C5 levels anteriorly. Electromyographic responses were measured in arm and hand muscles across a range of stimulus intensities. Double-pulse experiments were performed to assess homosynaptic post-activation depression (PAD). Safety was closely monitored. RESULTS: More than 170 cTSS sessions were conducted without major safety or tolerability issues. A cathode-posterior, 2 ms biphasic waveform provided optimal stimulation characteristics. Bilateral upper extremity muscle responses were easily obtained in subjects with SCI and ALS. Resting motor threshold at the abductor pollicis brevis muscle ranged from 5.5 to 51.0 mA. As stimulus intensity increased, response latencies to all muscles decreased. PAD was incomplete at lower stimulus intensities, and decreased at higher stimulus intensities. CONCLUSIONS: Posteroanterior cTSS has the capability to target motor neurons both trans-synaptically via large-diameter afferents and non-synaptically via efferent motor axons. SIGNIFICANCE: Posteroanterior cTSS is well tolerated and easily activates upper extremity muscles in individuals with SCI and ALS.

The Genetic Basis of Pericentral Retinitis Pigmentosa-A Form of Mild Retinitis Pigmentosa.

Pericentral retinitis pigmentosa (RP) is an atypical form of RP that affects the near-peripheral retina first and tends to spare the far periphery. This study was performed to further define the genetic basis of this phenotype. We identified a cohort of 43 probands with pericentral RP based on a comprehensive analysis of their retinal phenotype. Genetic analyses of DNA samples from these patients were performed using panel-based next-generation sequencing, copy number variations, and whole exome sequencing (WES). Mutations provisionally responsible for disease were found in 19 of the 43 families (44%) analyzed. These include mutations in RHO (five patients), USH2A (four patients), and PDE6B (two patients). Of 28 putatively pathogenic alleles, 15 (54%) have been previously identified in patients with more common forms of typical RP, while the remaining 13 mutations (46%) were novel. Burden testing of WES data successfully identified HGSNAT as a cause of pericentral RP in at least two patients, suggesting it is also a relatively common cause of pericentral RP. While additional sequencing might uncover new genes specifically associated with pericentral RP, the current results suggest that genetically pericentral RP is not a separate clinical entity, but rather is part of the spectrum of mild RP phenotypes.

Sensitive detection of Escherichia coli O157:H7 by conventional plating techniques.

The direct detection and estimation of concentration of Escherichia coli O157:H7 down to 1 CFU/g of cheese was achieved by conventional plating techniques. Cheese was manufactured with unpasteurized milk inoculated with E. coli O157: H7 at 34 +/- 3 CFU/ml. The numbers of E. coli O157:H7 were monitored during cheese ripening by plating on sorbitol MacConkey agar supplemented with cefixime and potassium tellurite (CT-SMAC) and on CT-O157:H7 ID medium. Using the pour plate method, E. coli O157:H7 colonies could easily be distinguished from non-O157:H7 colonies on CT-O157:H7 ID medium but not on CT-SMAC. Higher numbers of E. coli O157:H7 were detectable with O157:H7 ID medium. Latex agglutination and PCR were used to confirm the identification of typical E. coli O157:H7 colonies, and nontypical colonies as not being E. coli O157:H7. As few as 1 CFU/g of cheese could be detected. E. coli O157:H7 also was detected in deliberately contaminated milk at concentrations as low as 4 CFU/10 ml.