A common goodness-of-fit framework for neural population models using marked point process time-rescaling

A critical component of any statistical modeling procedure is the ability to assess the goodness-of-fit between a model and observed data. For spike train models of individual neurons, many goodness-of-fit measures rely on the time-rescaling theorem and assess model quality using rescaled spike times. Recently, there has been increasing interest in statistical models that describe the simultaneous spiking activity of neuron populations, either in a single brain region or across brain regions. Classically, such models have used spike sorted data to describe relationships between the identified neurons, but more recently clusterless modeling methods have been used to describe population activity using a single model. Here we develop a generalization of the time-rescaling theorem that enables comprehensive goodness-of-fit analysis for either of these classes of population models. We use the theory of marked point processes to model population spiking activity, and show that under the correct model, each spike can be rescaled individually to generate a uniformly distributed set of events in time and the space of spike marks. After rescaling, multiple well-established goodness-of-fit procedures and statistical tests are available. We demonstrate the application of these methods both to simulated data and real population spiking in rat hippocampus. We have made the MATLAB and Python code used for the analyses in this paper publicly available through our Github repository at https://github.com/Eden-Kramer-Lab/popTRT.This work was supported by grants from the NIH (MH105174, NS094288) and the Simons Foundation (542971). (MH105174 - NIH; NS094288 - NIH; 542971 - Simons Foundation)Published versio

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 ] HEALTH ]F2 ]2009 ]223175). The CIMBA data management and data analysis were supported by Cancer Research.UK grants 12292/A11174 and C1287/A10118. The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME ]ON Post ]GWAS Initiative (U19 ]CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute (dbGap accession number phs000178.v8.p7). The cBio portal is developed and maintained by the Computational Biology Center at Memorial Sloan ] Kettering Cancer Center. SH is supported by an NHMRC Program Grant to GCT. Details of the funding of individual investigators and studies are provided in the Supplementary Note. This study made use of data generated by the Wellcome Trust Case Control consortium, funding for which was provided by the Wellcome Trust under award 076113. The results published here are, in part, based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancerhttp://dx.doi.org/10.1038/ng.3185This is the Author Accepted Manuscript of 'Identification of six new susceptibility loci for invasive epithelial ovarian cancer' which was published in Nature Genetics 47, 164–171 (2015) © Nature Publishing Group - content may only be used for academic research

Performance of Breast Cancer Polygenic Risk Scores in 760 FemaleCHEK2Germline Mutation Carriers

Background: Genome-wide association studies suggest that the combined effects of breast cancer (BC)-associated single nucleotide polymorphisms (SNPs) can improve BC risk stratification using polygenic risk scores (PRSs). The performance of PRSs in genome-wide association studies-independent clinical cohorts is poorly studied in individuals carrying mutations in moderately penetrant BC predisposition genes such as CHEK2. Methods: A total of 760 female CHEK2 mutation carriers were included; 561 women were affected with BC, of whom 74 developed metachronous contralateral BC (mCBC). For PRS calculations, 2 SNP sets covering 77 (SNP set 1, developed for BC risk stratification in women unselected for their BRCA1/2 germline mutation status) and 88 (SNP set 2, developed for BC risk stratification in female BRCA1/2 mutation carriers) BC-associated SNPs were used. All statistical tests were 2-sided. Results: Both SNP sets provided concordant PRS results at the individual level (r = 0.91, P < 2.20 x 10(-16)). Weighted cohort Cox regression analyses revealed statistically significant associations of PRSs with the risk for first BC. For SNP set 1, a hazard ratio of 1.71 per SD of the PRS was observed (95% confidence interval =1.36 to 2.15, P = 3.87 x 10(-6)). PRSs identify a subgroup of CHEK2 mutation carriers with a predicted lifetime risk for first BC that exceeds the surveillance thresholds defined by international guidelines. Association of PRS with mCBC was examined via Cox regression analysis (SNP set 1 hazard ratio = 1.23, 95% confidence interval = 0.86 to 1.78, P = .26). Conclusions: PRSs may be used to personalize risk-adapted preventive measures for women with CHEK2 mutations. Larger studies are required to assess the role of PRSs in mCBC predisposition

Performance of Breast Cancer Polygenic Risk Scores in 760 Female CHEK2 Germline Mutation Carriers.

BACKGROUND: Genome-wide association studies suggest that the combined effects of breast cancer (BC)-associated single nucleotide polymorphisms (SNPs) can improve BC risk stratification using polygenic risk scores (PRSs). The performance of PRSs in genome-wide association studies-independent clinical cohorts is poorly studied in individuals carrying mutations in moderately penetrant BC predisposition genes such as CHEK2. METHODS: A total of 760 female CHEK2 mutation carriers were included; 561 women were affected with BC, of whom 74 developed metachronous contralateral BC (mCBC). For PRS calculations, 2 SNP sets covering 77 (SNP set 1, developed for BC risk stratification in women unselected for their BRCA1/2 germline mutation status) and 88 (SNP set 2, developed for BC risk stratification in female BRCA1/2 mutation carriers) BC-associated SNPs were used. All statistical tests were 2-sided. RESULTS: Both SNP sets provided concordant PRS results at the individual level (r = 0.91, P < 2.20 × 10-16). Weighted cohort Cox regression analyses revealed statistically significant associations of PRSs with the risk for first BC. For SNP set 1, a hazard ratio of 1.71 per SD of the PRS was observed (95% confidence interval = 1.36 to 2.15, P = 3.87 × 10-6). PRSs identify a subgroup of CHEK2 mutation carriers with a predicted lifetime risk for first BC that exceeds the surveillance thresholds defined by international guidelines. Association of PRS with mCBC was examined via Cox regression analysis (SNP set 1 hazard ratio = 1.23, 95% confidence interval = 0.86 to 1.78, P = .26). CONCLUSIONS: PRSs may be used to personalize risk-adapted preventive measures for women with CHEK2 mutations. Larger studies are required to assess the role of PRSs in mCBC predisposition

15q13.3 microdeletions increase risk of idiopathic generalized epilepsy

We identified 15q13.3 microdeletions encompassing the CHRNA7 gene in 12 of 1,223 individuals with idiopathic generalized epilepsy (IGE), which were not detected in 3,699 controls (joint P = 5.32 x 10(-8)). Most deletion carriers showed common IGE syndromes without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia. Our results indicate that 15q13.3 microdeletions constitute the most prevalent risk factor for common epilepsies identified to date