Background Genome-wide association studies (GWAS) have had limited success when applied to complex diseases. Analyzing SNPs individually requires several large studies to integrate the often divergent results. In the presence of epistasis, multivariate approaches based on the linear model (including stepwise logistic regression) often have low sensitivity and generate an abundance of artifacts. Methods Recent advances in distributed and parallel processing spurred methodological advances in nonparametric statistics. U-statistics for structured multivariate data (μStat) are not confounded by unrealistic assumptions (e.g., linearity, independence). Results By incorporating knowledge about relationships between SNPs, μGWAS (GWAS based on μStat) can identify clusters of genes around biologically relevant pathways and pinpoint functionally relevant regions within these genes. Conclusion With this computational biostatistics approach increasing power and guarding against artifacts, personalized medicine and comparative effectiveness will advance while subgroup analyses of Phase III trials can now suggest risk factors for ad verse events and novel directions for drug development.
To enable fast uncertainty quantification of fluid flow in a discrete fracture network (DFN), we present two approaches to quickly compute fluid flow in DFNs using combinatorial optimization algorithms. Specifically, the presented Hanan Shortest Path Maxflow (HSPM) and Intersection Shortest Path Maxflow (ISPM) methods translate DFN geometries and properties to a graph on which a max flow algorithm computes a combinatorial flow, from which an overall fluid flow rate is estimated using a shortest path decomposition of this flow. The two approaches are assessed by comparing their predictions with results from explicit numerical simulations of simple test cases as well as stochastic DFN realizations covering a range of fracture densities. Both methods have a high accuracy and very low computational cost, which can facilitate much-needed in-depth analyses of the propagation of uncertainty in fracture and fracture-network properties to fluid flow rates.
Most breast cancer deaths are caused by metastasis and treatment options beyond radiation and cytotoxic drugs, which have severe side effects, and hormonal treatments, which are or become ineffective for many patients, are urgently needed. This study reanalyzed existing data from three genome-wide association studies (GWAS) using a novel computational biostatistics approach (muGWAS), which had been validated in studies of 600–2000 subjects in epilepsy and autism. MuGWAS jointly analyzes several neighboring single nucleotide polymorphisms while incorporating knowledge about genetics of heritable diseases into the statistical method and about GWAS into the rules for determining adaptive genome-wide significance. Results from three independent GWAS of 1000–2000 subjects each, which were made available under the National Institute of Health’s “Up For A Challenge” (U4C) project, not only confirmed cell-cycle control and receptor/AKT signaling, but, for the first time in breast cancer GWAS, also consistently identified many genes involved in endo-/exocytosis (EEC), most of which had already been observed in functional and expression studies of breast cancer. In particular, the findings include genes that translocate (ATP8A1, ATP8B1, ANO4, ABCA1) and metabolize (AGPAT3, AGPAT4, DGKQ, LPPR1) phospholipids entering the phosphatidylinositol cycle, which controls EEC. These novel findings suggest scavenging phospholipids as a novel intervention to control local spread of cancer, packaging of exosomes (which prepare distant microenvironment for organ-specific metastases), and endocytosis of β1 integrins (which are required for spread of metastatic phenotype and mesenchymal migration of tumor cells). Beta-cyclodextrins (βCD) have already been shown to be effective in in vitro and animal studies of breast cancer, but exhibits cholesterol-related ototoxicity. The smaller alpha-cyclodextrins (αCD) also scavenges phospholipids, but cannot fit cholesterol. An in-vitro study presented here confirms hydroxypropyl (HP)-αCD to be twice as effective as HPβCD against migration of human cells of both receptor negative and estrogen-receptor positive breast cancer. If the previous successful animal studies with βCDs are replicated with the safer and more effective αCDs, clinical trials of adjuvant treatment with αCDs are warranted. Ultimately, all breast cancer are expected to benefit from treatment with HPαCD, but women with triple-negative breast cancer (TNBC) will benefit most, because they have fewer treatment options and their cancer advances more aggressively.
We present a scalable approach for range and k nearest neighbor queries under computationally expensive metrics, like the continuous Fréchet distance on trajectory data. Based on clustering for metric indexes, we obtain a dynamic tree structure whose size is linear in the number of trajectories, regardless of the trajectory’s individual sizes or the spatial dimension, which allows one to exploit low “intrinsic dimensionality” of datasets for effective search space pruning. Since the distance computation is expensive, generic metric indexing methods are rendered impractical. We present strategies that (i) improve on known upper and lower bound computations, (ii) build cluster trees without any or very few distance calls, and (iii) search using bounds for metric pruning, interval orderings for reduction, and randomized pivoting for reporting the final results. We analyze the efficiency and effectiveness of our methods with extensive experiments on diverse synthetic and real-world datasets. The results show improvement over state-of-the-art methods for exact queries, and even further speedups are achieved for queries that may return approximate results. Surprisingly, the majority of exact nearest-neighbor queries on real datasets are answered without any distance computations.
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