Enhanced laser-induced damage performance of all-glass metasurfaces for energetic pulsed laser applications.

To fabricate optical components with surface layers compatible with high-power laser applications that may operate as antireflective coatings, polarization rotators, or harness physical anisotropy for other uses, metasurfaces are becoming an appealing candidate. In this study, large-beam (1.05 cm diameter) 351-nm laser-induced damage testing was performed on an all-glass metasurface structure composed of cone-like features with a subwavelength spacing of adjacent features. These structures were fabricated on untreated fused silica glass and damage tested, as were structures that were fabricated on fused silica glass that experienced a preliminary etching process to remove the surface Beilby layer that is characteristic of polished fused silica. The laser-induced damage onset for structures on untreated fused silica glass was 19.3J⋅c m -2, while the sample that saw an initial pretreatment etch exhibited an improved damage onset of 20.4J⋅c m -2, only 6% short of the reference pretreated glass damage onset of 21.7J⋅c m -2. For perspective, the National Ignition Facility operational average fluence at this wavelength and pulse length is about 10J/c m 2. At a fluence of 25.5J⋅c m -2, the reference (pretreated) fused silica initiated 5.2 damage sites per m m 2, while the antireflective metasurface sample with a preliminary etching process treatment initiated 9.8 damage sites per m m 2. These findings demonstrate that substrate-engraved metasurfaces are compatible with high energy and power laser applications, further broadening their application space.

Femtosecond damage experiments and modeling of broadband mid-infrared dielectric diffraction gratings.

High peak and average power lasers with high wall-plug efficiency, like the Big Aperture Thulium (BAT) laser, have garnered tremendous attention in laser technology. To meet the requirements of the BAT laser, we have developed low-dispersion reflection multilayer dielectric (MLD) gratings suitable for compression of high-energy pulses for operations at 2 micron wavelength. We carried out 10000-on-1 damage tests to investigate the fluence damage thresholds of the designed MLD gratings and mirrors, which were found between 100-230 mJ/cm2. An ultrashort pulsed laser (FWHM = 53 fs, λ = 1.9 µm) operating at 500 Hz was used in the serpentine raster scans. The atomic force microscope images of the damage sites show blister formation of the underlying layers at lower fluences but ablation of the grating pillars at higher fluences. We simulated the dynamic electronic excitation in the MLD optics with a finite-difference in the time domain approach in 2D. The simulation results agree well with the LIDT measurements and the observed blister formation. This model is able to evaluate the absolute LIDT of MLD gratings.

Review on the Use of Artificial Intelligence to Predict Fire Performance of Construction Materials and Their Flame Retardancy.

The evaluation and interpretation of the behavior of construction materials under fire conditions have been complicated. Over the last few years, artificial intelligence (AI) has emerged as a reliable method to tackle this engineering problem. This review summarizes existing studies that applied AI to predict the fire performance of different construction materials (e.g., concrete, steel, timber, and composites). The prediction of the flame retardancy of some structural components such as beams, columns, slabs, and connections by utilizing AI-based models is also discussed. The end of this review offers insights on the advantages, existing challenges, and recommendations for the development of AI techniques used to evaluate the fire performance of construction materials and their flame retardancy. This review offers a comprehensive overview to researchers in the fields of fire engineering and material science, and it encourages them to explore and consider the use of AI in future research projects.

Coupling buried etalon layers to an engraved metasurface for durable and large-aperture meta-optics.

Many optical applications that could potentially benefit from the design flexibility provided by the metasurface approach are being prohibited by the limited scalability of the fabrication and the robustness of the end-result structures when using a resonant meta-elements-based approach. An alternative demonstrated approach with superior scalability and robustness is substrate-engraved metasurfaces, based on medium mixing homogenization, yet it suffers from very limited optical response. Here we propose advancing this approach by coupling the metasurface with buried etalon layers, leading to enhancement in the optical response. A transfer matrix analysis is used to study the parameter space, predicting that the patterned reflectance values range of a beam shaper could be raised from only 4% to 30% when the metasurface is engraved in silica, and even up to 66% when engraved into higher-index oxides. Using the method proposed here, the phase difference range across the metasurface could be increased by 0.4 radians beyond the range achievable by a metasurface engraved in silica and could reach even higher values when embedded in higher-index materials. Full-wave numerical simulations are used to demonstrate a cylindrical metareflector and a metalens, further validating the analysis.

Optically Assisted Surface Functionalization for Protein Arraying in Aqueous Media.

Protein surface patterning is employed in a broad spectrum of applications ranging from protein microarray analysis to 2D cell organization. However, limitations arise because of the highly sensitive nature of proteins requiring careful handling to ensure their structural and functional integrity during the grafting process. Here, we describe a patterning protocol that keeps proteins in an aqueous environment during their immobilization, avoiding the loss of their biological activity. The procedure is based on the UV-mediated removal of polyethylene glycol self-assembled monolayers in a transparent microfluidic chamber, giving access to micrometric motifs of predefined geometries. Afterward, modified proteins can be grafted on the photopatterned domains. We also studied the influence of reactive oxygen species for a better understanding of the chemical mechanism involved in this process. Finally, as a proof of concept, a protein microarray was created with this process using cell-capturing antibodies to immobilize human blood cells, confirming the functionality of the arrayed proteins.

The Impact of Socioeconomic Status on Appendiceal Perforation in Pediatric Appendicitis.

OBJECTIVE: To assess the impact of socioeconomic status (SES) on pediatric appendicitis outcomes using the validated Agency for Healthcare Research and Quality (AHRQ) SES Index and incorporating block-group data. STUDY DESIGN: We reviewed all patients <18 years old who underwent appendectomy for acute appendicitis from 2009-2013 at our institution. Patient addresses were geocoded and linked to 2010 US Census SES block-group data to determine composite AHRQ SES Index scores based on 7 publically reported SES variables. The primary outcome was appendiceal perforation, and the impact of SES scores, age, race, and insurance status on perforation rates were assessed through regression analyses. RESULTS: Of 1501 patients, 510 (34%) had perforated appendicitis. On bivariate analysis, components of the SES Index associated with an increased perforation rate included lower household income, lower percentage of adults with college education, and higher percentage of adults with <12th grade education (all P < .05). On multivariate analysis, age ≤ 10 years (OR 1.7, 95% CI 1.4-2.2) and public insurance (OR 1.5, 95% CI 1.2-2.0) were associated with increased odds of perforation. CONCLUSIONS: This study used the AHRQ SES scoring system to evaluate SES and its influence on appendiceal perforation. Among our cohort of pediatric patients, the risk of perforation was multifactorial, and younger age and public insurance were stronger predictors of perforation than SES.

Health Disparities Influence Childhood Melanoma Stage at Diagnosis and Outcome.

OBJECTIVE: To identify health disparities in pediatric patients with melanoma that affect disease presentation and outcome. STUDY DESIGN: This was a retrospective cohort study of all persons aged ≤18 years diagnosed with melanoma and enrolled in the Texas Cancer Registry between 1995 and 2009. Socioeconomic status (SES) and driving distance to the nearest pediatric cancer treatment center were calculated for each patient. Logistic regression was used to determine factors associated with advanced-stage disease. Life table methods and Cox regression were used to estimate survival probability and hazard ratios. RESULTS: A total of 185 adolescents (age >10 years) and 50 young children (age ≤10 years) were identified. Hispanics (n = 27; 12%) were 3 times more likely than non-Hispanic whites (n = 177; 75%) to present with advanced disease (OR, 3.8; 95% CI, 1.7-8.8). Young children were twice as likely as adolescents to present with advanced disease (OR, 2.2; 95% CI, 1.1-4.3). Distance to treatment center and SES did not affect stage of disease at presentation. Hispanics and those in the lowest SES quartile had a significantly higher mortality risk (hazard ratios, 3.0 [95% CI, 1.2-7.8] and 4.3 [95% CI, 1.4-13.9], respectively). In the adjusted survival model, only advanced disease was predictive of mortality (P < .001). CONCLUSION: Hispanics and young children with melanoma are more likely to present with advanced disease, and advanced disease is the single most important predictor of survival. Heightened awareness among physicians is needed to facilitate early detection of melanoma within these groups.

Active cooling of pulse compression diffraction gratings for high energy, high average power ultrafast lasers.

Laser energy absorption and subsequent heat removal from diffraction gratings in chirped pulse compressors poses a significant challenge in high repetition rate, high peak power laser development. In order to understand the average power limitations, we have modeled the time-resolved thermo-mechanical properties of current and advanced diffraction gratings. We have also developed and demonstrated a technique of actively cooling Petawatt scale, gold compressor gratings to operate at 600W of average power - a 15x increase over the highest average power petawatt laser currently in operation. Combining this technique with low absorption multilayer dielectric gratings developed in our group would enable pulse compressors for petawatt peak power lasers operating at average powers well above 40kW.

Low rates of bone mineral density measurement in Medicare beneficiaries with prostate cancer initiating androgen deprivation therapy.

BACKGROUND: Men with prostate cancer who undergo androgen deprivation therapy (ADT) are at risk for bone loss and fractures. Our objective was to determine if Medicare beneficiaries with prostate cancer in the state of Texas underwent DXA scans when initiating ADT. METHODS: We identified men diagnosed with prostate cancer between 2005 and 2007 in the Texas Cancer Registry/Medicare linked database, and who received parenteral ADT or orchiectomy. We identified DXA claims within 1 year before or 6 months after starting ADT. We examined use of bone conservation agents in the subgroup of patients enrolled in Medicare Part D. Multivariate logistic regression models were used to examine determinants of DXA use. RESULTS: The analysis included 2,290 men (2,262 parenteral ADT, 28 orchiectomy); 197 (8.6 %) underwent DXA within 1 year before and 6 months after starting ADT. Men aged 75 years or older were more likely to undergo DXA than men aged 66-74 years (OR 1.5; 95 % CI 1.1-2.1). Those living in small urban areas were less likely to undergo DXA than those in big areas (OR 0.40; 95 % CI 0.19-0.82). Of the 1,060 men enrolled in Medicare part D, 59 (5.6 %) received bone conservation agents when starting ADT; 134 (12.6 %) either received bone conservation agents or underwent DXA. CONCLUSIONS: Fewer than one in ten Medicare beneficiaries with prostate cancer initiating ADT underwent a DXA exam. Variation in utilization was also related to residence area size. Further research is needed to identify whether the use of DXA in patients with prostate cancer receiving ADT will result in fracture prevention.

Self-reported physical activity among middle-aged cancer survivors in the United States: Behavioral Risk Factor Surveillance System Survey, 2009.

INTRODUCTION: Regular physical activity (PA) can improve health outcomes in cancer survivors, but the rate of adherence to PA recommendations among middle-aged survivors is unclear. We examined adherence to PA recommendations among cancer survivors and controls. We sought to identify correlates of adherence to PA and to determine whether PA adherence is associated with health-related quality of life (HRQOL) among cancer survivors. METHODS: We examined PA adherence among 8,655 cancer survivors and 144,213 control subjects aged 45-64 years who were respondents to the 2009 Behavior Risk Factor Surveillance System survey. We used multinomial logistic regression to assess associations between PA adherence and demographic, psychosocial, and clinical factors, and multivariable linear regression to assess the relationship between PA adherence and HRQOL of cancer survivors. RESULTS: Cancer survivors and control subjects had similar rates of PA adherence. Of the survivors, 47% met the recommendations of 150 minutes of moderate-intensity PA or 120 minutes of vigorous-intensity PA per week, 41% were somewhat active, and 12% were sedentary. Compared with cancer survivors who were sedentary, survivors who were somewhat active were less likely to be obese (odds ratio [OR], 0.65; P < .007), and those who met PA recommendations were less likely to be overweight (OR, 0.61; P < .002) or obese (OR, 0.33, P < .001). Regression analysis indicated that PA adherence was positively correlated with HRQOL (P < .001). CONCLUSION: Most cancer survivors did not meet PA recommendations, but those who are active seem to have improved HRQOL. Therefore, targeted interventions to improve adherence to PA among cancer survivors are needed.

Selective capture of carbon dioxide under humid conditions by hydrophobic chabazite-type zeolitic imidazolate frameworks.

Hydrophobic zeolitic imidazolate frameworks (ZIFs) with the chabazite (CHA) topology are synthesized by incorporating two distinct imidazolate links. Zn(2-mIm)0.86 (bbIm)1.14 (ZIF-300), Zn(2-mIm)0.94 (cbIm)1.06 (ZIF-301), and Zn(2-mIm)0.67 (mbIm)1.33 (ZIF-302), where 2-mIm = 2-methylimidazolate, bbIm = 5(6)-bromobenzimidazolate, cbIm = 5(6)-chlorobenzimidazolate, and mbIm = 5(6)-methylbenzimidazolate, were prepared by reacting zinc nitrate tetrahydrate and 2-mIm with the respective bIm link in a mixture of N,N-dimethylformamide (DMF) and water. Their structures were determined by single-crystal X-ray diffraction and their permanent porosity shown. All of these structures are hydrophobic as confirmed by water adsorption isotherms. All three ZIFs are equally effective at the dynamic separation of CO2 from N2 under both dry and humid conditions without any loss of performance over three cycles and can be regenerated simply by using a N2 flow at ambient temperature.

Declining mortality rates despite increases in clinical coronary artery disease among US dialysis patients: a national registry study.

BACKGROUND/AIMS: Coronary artery disease (CAD) is a major risk factor for death on dialysis. The objective of this study was to compare prevalent trends and patterns of survival in successive national cohorts. METHODS: National data on 823,753 incident dialysis patients, aged 18 and over, were analyzed from the US Renal Data System from 1995 to 2004. The prevalence of CAD was compared across calendar years by sex and race categorized as; White, Black, Asian and Native American/Alaskan Native (Native Am). Two-year mortality rates were determined for annual cohorts and multivariable Cox regression compared hazard ratios (HR) and 95% confidence intervals. RESULTS: From 1995 to 2004, the annual prevalence of CAD increased significantly in men from 25.2 to 30.1% and in women from 22.1 to 25.3%, p < 0.001. For men, the rise in prevalence was largely due to increases among Black men and older White men. For women, the pattern was similar. During this period, death rates decreased significantly from 379 to 348 and from 396 to 357 per 1,000 person-years in men and women respectively. Multivariate analysis identified significant reductions in mortality with advancing calendar year for White (HR 0.98 (0.98-0.99)), Asian (HR 0.93 (0.91-0.96)), and Native Am men (HR 0.95 (0.90-0.99)), and for White (HR 0.99 (0.98-0.99)) and Native Am women (HR 0.93 (0.89-0.98)). No significant trends were observed for Black patients. CONCLUSIONS: Despite a rising burden of CAD among incident US dialysis patients, mortality rates have fallen for most groups. Substantial racial disparities remain.

Birefringent Glass-Engraved Tilted Pillar Metasurfaces for High Power Laser Applications.

Birefringent materials-which are highly needed in high power laser systems-may be limited in usage due to the laser-induced damage threshold of traditional birefringent materials. This work reports here on all-glass metasurfaces, fabricated by angled etching through sacrificial metal nanoparticle (NP) etching masks, for generation of effective birefringence in the formed layer. As a result, a fused silica metasurface, monolithic to the underlying substrate, is demonstrated to exhibit a birefringence of 6.57° under 375 nm illumination. Full-wave analysis shows a good agreement with the measurement and presents potential paths forward to increasing the effective metasurface birefringence. This is the first demonstration, to the best of knowledge, of an etching technique to obtain the resulting tilted pillar-like nanofeatures. The anisotropy of the metasurface nanoelements along the two window in-plane major axes presents different effective paths for the two polarizations and thus generates birefringence in a nonbirefringent material. Additionally, the imparted anisotropy lends itself to manipulation of physical properties of the surface as well, with metasurface feature orientation suppressing water flow along one principal axis and giving rise to water flow steering capabilities.

The Influence of Comorbidities, General Health Status, and Self-Care Self-Efficacy on COVID-19 Symptoms During the Omicron Wave.

Background The emergence of the less virulent COVID-19 strains such as Omicron and its subvariants shifted the paradigm of COVID-19 treatment from inpatient treatment to regular outpatient care. The individual health determinants affecting COVID-19 disease severity among vulnerable adults treated in outpatient settings are an under-researched area. Methods This study conducted in an outpatient COVID-19 antibody infusion center employed a cross-sectional survey design to explore the impact of comorbidities, general health status, and self-care self-efficacy on COVID-19 symptom severity. We recruited 120 COVID-19-positive participants over 40 years of age, of which 117 completed the study with 87 providing complete data. After the screening and consenting process, the participants completed the following surveys in a secure REDCap survey software (Vanderbilt University, Nashville, USA) on an iPad (Apple Inc., Cupertino, USA): 1) sociodemographic questionnaire, 2) Charlson Comorbidity Index (CCI) to capture comorbidities, 3) Medical Outcomes Study Short-Form (SF-12) to assess general health including physical (PCS) and mental (MCS) health subscales, 4) Self-Care Self-Efficacy Scale (SCSES) to measure self-care self-efficacy, and 5) the COVID-19 Symptom rating scale (COVID-19 SRS). Statistical analysis used were Chi-square and Pearson correlations.  Results As evidenced by CCI, the top five comorbidities were hypertension (42%), diabetes mellitus (31%), pulmonary disease (19%), depression (14%), and solid tumors (11%). Age was statistically significantly correlated to comorbidity burden (p<0.0001). Severe COVID-19 symptoms reported were fatigue, myalgia, cough, runny nose, and sore throat. The general health status measure (SF-12) subscales showed that the patient's mental component summary (MCS) was more statistically significant to COVID-19 symptom severity than the physical component summary (PCS). The MCS demonstrated a statistically significant correlation with fatigue and myalgia (p<0.0001), headache and breathing difficulties (p<0.001), nausea/vomiting (p<0.01), and abdominal pain/diarrhea (p<0.05). The PCS showed a lesser statistically significant correlation with fatigue, myalgia, headaches (p<0.01), fever/chills, cough, congestion/runny nose, night sweats, breathing difficulties, nausea/vomiting, and abdominal pain/diarrhea (p<0.05). Interestingly, the 'loss of smell' which is the hallmark symptom of COVID-19 was the only symptom that showed a statically significant correlation with the Charlson Comorbidity Index (p<0.05), and it did not show any association with either mental (SF-12 MCS) or physical (SF-12 PCS) health status. The SF-12 MCS also showed a statistically significant correlation with a diagnosis of depression (p< 0.01), validating it as a true measure of mental health among vulnerable adults. The SCSES was not correlated with any of the COVID-19 symptoms. Conclusions The patient's general health status, especially mental health was more statistically significant to COVID-19 symptoms. The COVID-19 hallmark symptom of 'loss of smell' was the only symptom that showed statistical significance with comorbidities. Within the limitations of a cross-sectional survey design and convenient sampling methods, this study calls to tailor general health status, especially mental health, and cumulative comorbidity burden to risk assessment/risk stratification of COVID-19 care.

The impact of chronic obstructive pulmonary disease and smoking on mortality and kidney transplantation in end-stage kidney disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and tobacco use are leading causes of morbidity and mortality. The prevalence and clinical impact of COPD on mortality and kidney transplantation among patients who begin dialysis therapy is unclear. METHODS: We explored the clinical impact of COPD and continued tobacco use on overall mortality and kidney transplantation in a national cohort study of US dialysis patients. National data on all dialysis patients (n = 769,984), incident between May 1995 and December 2004 and followed until October 31, 2006, were analyzed from the United States Renal Data System. Prevalence and period trends were determined while multivariable Cox regression evaluated relative hazard ratios (RR) for death and kidney transplantation. RESULTS: The prevalence of COPD was 7.5% overall and increased from 6.7 to 8.1% from 1995-2004. COPD correlated significantly with older age, cardiovascular conditions, cancer, malnutrition, poor functional status, and tobacco use. Adjusted mortality risks were significantly higher for patients with COPD (RR = 1.20, 95% CI 1.18-1.21), especially among current smokers (RR = 1.28, 95% CI 1.25-1.32), and varied inversely with advancing age. In contrast, the adjusted risks of kidney transplantation were significantly lower for patients with COPD (RR = 0.47, 95% CI 0.41-0.54, for smokers and RR = 0.54, 95% CI 0.50-0.58, for non-smokers) than without COPD [RR = 0.72, 95% CI 0.70-0.75, for smokers and RR = 1.00 for non-smokers (referent category)]. CONCLUSIONS: Patients with COPD who begin dialysis therapy in the US experience higher mortality and lower rates of kidney transplantation, outcomes that are far worse among current smokers.

Plasmon resonant cavities in vertical nanowire arrays.

We investigate tunable plasmon resonant cavity arrays in paired parallel nanowire waveguides. Resonances are observed when the waveguide length is an odd multiple of quarter plasmon wavelengths, consistent with boundary conditions of node and antinode at the ends. Two nanowire waveguides satisfy the dispersion relation of a planar metal-dielectric-metal waveguide of equivalent width equal to the square field average weighted gap. Confinement factors over 10(3) are possible due to plasmon focusing in the interwire space.

Analysis of Genetically Regulated Gene Expression Identifies a Prefrontal PTSD Gene, SNRNP35, Specific to Military Cohorts.

To reveal post-traumatic stress disorder (PTSD) genetic risk influences on tissue-specific gene expression, we use brain and non-brain transcriptomic imputation. We impute genetically regulated gene expression (GReX) in 29,539 PTSD cases and 166,145 controls from 70 ancestry-specific cohorts and identify 18 significant GReX-PTSD associations corresponding to specific tissue-gene pairs. The results suggest substantial genetic heterogeneity based on ancestry, cohort type (military versus civilian), and sex. Two study-wide significant PTSD associations are identified in European and military European cohorts; ZNF140 is predicted to be upregulated in whole blood, and SNRNP35 is predicted to be downregulated in dorsolateral prefrontal cortex, respectively. In peripheral leukocytes from 175 marines, the observed PTSD differential gene expression correlates with the predicted differences for these individuals, and deployment stress produces glucocorticoid-regulated expression changes that include downregulation of both ZNF140 and SNRNP35. SNRNP35 knockdown in cells validates its functional role in U12-intron splicing. Finally, exogenous glucocorticoids in mice downregulate prefrontal Snrnp35 expression.

Scalable Light-Printing of Substrate-Engraved Free-Form Metasurfaces.

A key challenge for metasurface research is locally controlling at will the nanoscale geometric features on meter-scale apertures. Such a technology is expected to enable large aperture meta-optics and revolutionize fields such as long-range imaging, lasers, laser detection and ranging (LADAR), and optical communications. Furthermore, these applications are often more sensitive to light-induced and environmental degradation, which constrains the possible materials and fabrication process. Here, we present a relatively simple and scalable method to fabricate a substrate-engraved metasurface with locally printed index determined by induced illumination, which, therefore, addresses both the challenges of scalability and durability. In this process, a thin metal film is deposited onto a substrate and transformed into a mask via local laser-induced dewetting into nanoparticles. The substrate is then dry-etched through this mask, and selective mask removal finally reveals the metasurface. We show that masking by the local nanoparticle distribution, and, therefore, the local index, is dependent on the local light-induced dewetting temperature. We demonstrate printing of a free-form pattern engraved into a fused silica glass substrate using a laser raster scan. Large-scale spatially controlled engraving of metasurfaces has implications on other technological fields beyond optics, such as surface fluidics, acoustics, and thermomechanics.

The Role of Water in Mediating Interfacial Adhesion and Shear Strength in Graphene Oxide.

Graphene oxide (GO), whose highly tunable surface chemistry enables the formation of strong interfacial hydrogen-bond networks, has garnered increasing interest in the design of devices that operate in the presence of water. For instance, previous studies have suggested that controlling GO's surface chemistry leads to enhancements in interfacial shear strength, allowing engineers to manage deformation pathways and control failure mechanisms. However, these previous reports have not explored the role of ambient humidity and only offer extensive chemical modifications to GO's surface as the main pathway to control GO's interfacial properties. Herein, through atomic force microscopy experiments on GO-GO interfaces, the adhesion energy and interfacial shear strength of GO were measured as a function of ambient humidity. Experimental evidence shows that adhesion energy and interfacial shear strength can be improved by a factor of 2-3 when GO is exposed to moderate (∼30% water weight) water content. Furthermore, complementary molecular dynamics simulations uncovered the mechanisms by which these nanomaterial interfaces achieve their properties. They reveal that the strengthening mechanism arises from the formation of strongly interacting hydrogen-bond networks, driven by the chemistry of the GO basal plane and intercalated water molecules between two GO surfaces. In summary, the methodology and findings here reported provide pathways to simultaneously optimize GO's interfacial and in-plane mechanical properties, by tailoring the chemistry of GO and accounting for water content, in engineering applications such as sensors, filtration membranes, wearable electronics, and structural materials.

Integrated Bayesian analysis of rare exonic variants to identify risk genes for schizophrenia and neurodevelopmental disorders.

BACKGROUND: Integrating rare variation from trio family and case-control studies has successfully implicated specific genes contributing to risk of neurodevelopmental disorders (NDDs) including autism spectrum disorders (ASD), intellectual disability (ID), developmental disorders (DDs), and epilepsy (EPI). For schizophrenia (SCZ), however, while sets of genes have been implicated through the study of rare variation, only two risk genes have been identified. METHODS: We used hierarchical Bayesian modeling of rare-variant genetic architecture to estimate mean effect sizes and risk-gene proportions, analyzing the largest available collection of whole exome sequence data for SCZ (1,077 trios, 6,699 cases, and 13,028 controls), and data for four NDDs (ASD, ID, DD, and EPI; total 10,792 trios, and 4,058 cases and controls). RESULTS: For SCZ, we estimate there are 1,551 risk genes. There are more risk genes and they have weaker effects than for NDDs. We provide power analyses to predict the number of risk-gene discoveries as more data become available. We confirm and augment prior risk gene and gene set enrichment results for SCZ and NDDs. In particular, we detected 98 new DD risk genes at FDR < 0.05. Correlations of risk-gene posterior probabilities are high across four NDDs (ρ>0.55), but low between SCZ and the NDDs (ρ<0.3). An in-depth analysis of 288 NDD genes shows there is highly significant protein-protein interaction (PPI) network connectivity, and functionally distinct PPI subnetworks based on pathway enrichment, single-cell RNA-seq cell types, and multi-region developmental brain RNA-seq. CONCLUSIONS: We have extended a pipeline used in ASD studies and applied it to infer rare genetic parameters for SCZ and four NDDs ( https://github.com/hoangtn/extTADA ). We find many new DD risk genes, supported by gene set enrichment and PPI network connectivity analyses. We find greater similarity among NDDs than between NDDs and SCZ. NDD gene subnetworks are implicated in postnatally expressed presynaptic and postsynaptic genes, and for transcriptional and post-transcriptional gene regulation in prenatal neural progenitor and stem cells.