Rank-invariant estimation of inbreeding coefficients.

The two alleles an individual carries at a locus are identical by descent (ibd) if they have descended from a single ancestral allele in a reference population, and the probability of such identity is the inbreeding coefficient of the individual. Inbreeding coefficients can be predicted from pedigrees with founders constituting the reference population, but estimation from genetic data is not possible without data from the reference population. Most inbreeding estimators that make explicit use of sample allele frequencies as estimates of allele probabilities in the reference population are confounded by average kinships with other individuals. This means that the ranking of those estimates depends on the scope of the study sample and we show the variation in rankings for common estimators applied to different subdivisions of 1000 Genomes data. Allele-sharing estimators of within-population inbreeding relative to average kinship in a study sample, however, do have invariant rankings across all studies including those individuals. They are unbiased with a large number of SNPs. We discuss how allele sharing estimates are the relevant quantities for a range of empirical applications.

ASAFE: ancestry-specific allele frequency estimation.

UNLABELLED: In a genome-wide association study (GWAS) of an admixed population, such as Hispanic Americans, ancestry-specific allele frequencies can inform the design of a replication GWAS. We derive an EM algorithm to estimate ancestry-specific allele frequencies for a bi-allelic marker given genotypes and local ancestries on a 3-way admixed population, when the phase of each admixed individual's genotype relative to the pair of local ancestries is unknown. We call our algorithm Ancestry Specific Allele Frequency Estimation (ASAFE). We demonstrate that ASAFE has low error on simulated data. AVAILABILITY AND IMPLEMENTATION: The R source code for ASAFE is available for download at https://github.com/BiostatQian/ASAFE CONTACT: qszhang@uw.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Immunotherapy and Radiotherapy Combinations for Sarcoma.

Sarcomas are a heterogeneous group of bone and soft tissue tumors. Survival outcomes for advanced (unresectable or metastatic) disease remain poor, so therapeutic improvements are needed. Radiotherapy plays an integral role in the neoadjuvant and adjuvant treatment of localized disease as well as in the treatment of metastatic disease. Combining radiotherapy with immunotherapy to potentiate immunotherapy has been used in a variety of cancers other than sarcoma, and there is opportunity to further investigate combining immunotherapy with radiotherapy to try to improve outcomes in sarcoma. In this review, we describe the diversity of the tumor immune microenvironments for sarcomas and describe the immunomodulatory effects of radiotherapy. We discuss studies on the timing of radiotherapy relative to immunotherapy and studies on the radiotherapy dose and fractionation regimen to be used in combination with immunotherapy. We describe the impact of radiotherapy on the tumor immune microenvironment. We review completed and ongoing clinical trials combining radiotherapy with immunotherapy for sarcoma and propose future directions for studies combining immunotherapy with radiotherapy in the treatment of sarcoma.

Fédération Nationale Des Centres de Lutte Contre Le Cancer (FNCLCC) Grading, Margin Status and Tumor Location Associate With Survival Outcomes in Malignant Peripheral Nerve Sheath Tumors.

BACKGROUND: Histologic grading using the Fédération Nationale des Centres de Lutte Contre Le Cancer (FNCLCC) system is not universally accepted as applicable to malignant peripheral nerve sheath tumor (MPNST), as its prognostic value is not well established. METHODS: We retrospectively evaluated 99 cases of MPNST to investigate any association between the outcomes overall survival (OS) and progression-free survival (PFS), and predictor variables FNCLCC grade, clinical setting, tumor location, and tumor size at diagnosis using multivariable Cox proportional hazard analysis. RESULTS: Univariable and multivariable analysis demonstrate a statistically significant association between FNCLCC grade and both OS and PFS when comparing tumors by histologic grade. Of note, no deaths were observed in patients with grade 1 MPNST. Other variables associated with unfavorable outcomes include fragmented resection and primary site, with tumors in the extremities having favorable OS, but not PFS, when compared with those in truncal locations. Tumors in the head and neck had favorable PFS, but not OS, compared with those in the trunk. No statistically significant differences in OS or PFS were observed when comparing patient age and sex, tumor size at diagnosis, clinical setting (primary vs. type-1 neurofibromatosis vs. radiation associated) or history of neoadjuvant therapy. Interobserver agreement for FNCLCC grading of these tumors was considered good (S*=0.77, 95% confidence interval: 0.71-0.84). CONCLUSIONS: Association between FNCLCC grading and survival outcomes in MPNST suggests potential value to routinely grading these neoplasms. However, the subjectivity of the grading system, particularly when assigning a tumor differentiation score, may pose a challenge, especially in low and intermediate grade lesions.

Genome-wide association study of heart rate and its variability in Hispanic/Latino cohorts.

BACKGROUND: Although time-domain measures of heart rate variability (HRV) are used to estimate cardiac autonomic tone and disease risk in multiethnic populations, the genetic epidemiology of HRV in Hispanics/Latinos has not been characterized. OBJECTIVE: The purpose of this study was to conduct a genome-wide association study of heart rate (HR) and its variability in the Hispanic Community Health Study/Study of Latinos, Multi-Ethnic Study of Atherosclerosis, and Women's Health Initiative Hispanic SNP-Health Association Resource project (n = 13,767). METHODS: We estimated HR (bpm), standard deviation of normal-to-normal interbeat intervals (SDNN, ms), and root mean squared difference in successive, normal-to-normal interbeat intervals (RMSSD, ms) from resting, standard 12-lead ECGs. We estimated associations between each phenotype and 17 million genotyped or imputed single nucleotide polymorphisms (SNPs), accounting for relatedness and adjusting for age, sex, study site, and ancestry. Cohort-specific estimates were combined using fixed-effects, inverse-variance meta-analysis. We investigated replication for select SNPs exceeding genome-wide (P <5 × 10-8) or suggestive (P <10-6) significance thresholds. RESULTS: Two genome-wide significant SNPs replicated in a European ancestry cohort, 1 one for RMSSD (rs4963772; chromosome 12) and another for SDNN (rs12982903; chromosome 19). A suggestive SNP for HR (rs236352; chromosome 6) replicated in an African-American cohort. Functional annotation of replicated SNPs in cardiac and neuronal tissues identified potentially causal variants and mechanisms. CONCLUSION: This first genome-wide association study of HRV and HR in Hispanics/Latinos underscores the potential for even modestly sized samples of non-European ancestry to inform the genetic epidemiology of complex traits.

Genome-wide haplotypic testing in a Finnish cohort identifies a novel association with low-density lipoprotein cholesterol.

We performed genome-wide tests for association between haplotype clusters and each of 9 metabolic traits in a cohort of 5402 Northern Finnish individuals genotyped for 330 000 single-nucleotide polymorphisms. The metabolic traits were body mass index, C-reactive protein, diastolic blood pressure, glucose, high-density lipoprotein (HDL), insulin, low-density lipoprotein (LDL), systolic blood pressure, and triglycerides. Haplotype clusters were determined using Beagle. There were LDL-associated clusters in the chromosome 4q13.3-q21.1 region containing the albumin (ALB) and platelet factor 4 (PF4) genes. This region has not been associated with LDL in previous genome-wide association studies. The most significant haplotype cluster in this region was associated with 0.488 mmol/l higher LDL (95% CI: 0.361-0.615 mmol/l, P-value: 6.4 × 10(-14)). We also observed three previously reported associations: Chromosome 16q13 with HDL, chromosome 1p32.3-p32.2 with LDL and chromosome 19q13.31-q13.32 with LDL. The chromosome 1 and chromosome 4 LDL associations do not reach genome-wide significance in single-marker analyses of these data, illustrating the power of haplotypic association testing.