Jan Christian Kässens

Development of a high-resolution NGS-based HLA-typing and analysis pipeline.

The human leukocyte antigen (HLA) complex contains the most polymorphic genes in the human genome. The classical HLA class I and II genes define the specificity of adaptive immune responses. Genetic variation at the HLA genes is associated with susceptibility to autoimmune and infectious diseases and plays a major role in transplantation medicine and immunology. Currently, the HLA genes are characterized using Sanger- or next-generation sequencing (NGS) of a limited amplicon repertoire or labeled oligonucleotides for allele-specific sequences. High-quality NGS-based methods are in proprietary use and not publicly available. Here, we introduce the first highly automated open-kit/open-source HLA-typing method for NGS. The method employs in-solution targeted capturing of the classical class I (HLA-A, HLA-B, HLA-C) and class II HLA genes (HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1, HLA-DPB1). The calling algorithm allows for highly confident allele-calling to three-field resolution (cDNA nucleotide variants). The method was validated on 357 commercially available DNA samples with known HLA alleles obtained by classical typing. Our results showed on average an accurate allele call rate of 0.99 in a fully automated manner, identifying also errors in the reference data. Finally, our method provides the flexibility to add further enrichment target regions.

Parallelizing Epistasis Detection in GWAS on FPGA and GPU-Accelerated Computing Systems

High-throughput genotyping technologies (such as SNP-arrays) allow the rapid collection of up to a few million genetic markers of an individual. Detecting epistasis (based on 2-SNP interactions) in Genome-Wide Association Studies is an important but time consuming operation since statistical computations have to be performed for each pair of measured markers. Computational methods to detect epistasis therefore suffer from prohibitively long runtimes; e.g., processing a moderately-sized dataset consisting of about 500,000 SNPs and 5,000 samples requires several days using state-of-the-art tools on a standard 3 GHz CPU. In this paper, we demonstrate how this task can be accelerated using a combination of fine-grained and coarse-grained parallelism on two different computing systems. The first architecture is based on reconfigurable hardware (FPGAs) while the second architecture uses multiple GPUs connected to the same host. We show that both systems can achieve speedups of around four orders-of-magnitude compared to the sequential implementation. This significantly reduces the runtimes for detecting epistasis to only a few minutes for moderatelysized datasets and to a few hours for large-scale datasets.

UPC++ for bioinformatics: A case study using genome-wide association studies

Modern genotyping technologies are able to obtain up to a few million genetic markers (such as SNPs) of an individual within a few minutes of time. Detecting epistasis, such as SNP-SNP interactions, in Genome-Wide Association Studies is an important but time-consuming operation since statistical computations have to be performed for each pair of measured markers. Therefore, a variety of HPC architectures have been used to accelerate these studies. In this work we present a parallel approach for multi-core clusters, which is implemented with UPC++ and takes advantage of the features available in the Partitioned Global Address Space and Object Oriented Programming models. Our solution is based on a well-known regression model (used by the popular BOOST tool) to test SNP-pairs interactions. Experimental results show that UPC++ is suitable for parallelizing data-intensive bioinformatics applications on clusters. For instance, it reduces the time to analyze a real-world dataset with more than 500,000 SNPs and 5,000 individuals from several days when using a single core to less than one minute using 512 nodes (12,288 cores) of a Cray XC30 supercomputer.

High-speed exhaustive 3-locus interaction epistasis analysis on FPGAs

Abstract Epistasis, the interaction between genes, has become a major topic in molecular and quantitative genetics. It is believed that these interactions play a significant role in genetic variations causing complex diseases. Several algorithms have been employed to detect pairwise interactions in genome-wide association studies (GWAS) but revealing higher order interactions remains a computationally challenging task. State of the art tools are not able to perform exhaustive search for all three-locus interactions in reasonable time even for relatively small input datasets. In this paper we present how a hardware-assisted design can solve this problem and provide fast, efficient and exhaustive third-order epistasis analysis with up-to-date FPGA technology.

Hybrid CPU/GPU Acceleration of Detection of 2-SNP Epistatic Interactions in GWAS

High-throughput genotyping technologies allow the collection of up to a few million genetic markers (such as SNPs) of an individual within a few minutes of time. Detecting epistasis, such as 2-SNP interactions, in Genome-Wide Association Studies is an important but time consuming operation since statistical computations have to be performed for each pair of measured markers. In this work we present EpistSearch, a parallelized tool that, following the log-linear model approach, uses a novel filter to determine the interactions between all SNP-pairs. Our tool is parallelized using a hybrid combination of Pthreads and CUDA in order to take advantage of CPU/GPU architectures. Experimental results with simulated and real datasets show that EpistSearch outperforms previous approaches, either using GPUs or only CPU cores. For instance, an exhaustive analysis of a real-world dataset with 500,000 SNPs and 5,000 individuals requires less than 42 minutes on a machine with 6 CPU cores and a GTX Titan GPU.

Large-scale genome-wide association studies on a GPU cluster using a CUDA-accelerated PGAS programming model

Detecting epistasis, such as 2-SNP interactions, in genome-wide association studies (GWAS) is an important but time consuming operation. Consequently, GPUs have already been used to accelerate these studies, reducing the runtime for moderately-sized datasets to less than 1 hour. However, single-GPU approaches cannot perform large-scale GWAS in reasonable time. In this work we present multiEpistSearch, a tool to detect epistasis that works on GPU clusters. While CUDA is used for parallelization within each GPU, the workload distribution among GPUs is performed with Unified Parallel C++ (UPC++), a novel extension of C++ that follows the Partitioned Global Address Space (PGAS) model. multiEpistSearch is able to analyze large-scale datasets with 5 million SNPs from 10,000 individuals in less than 3 hours using 24 NVIDIA GTX Titans.

Fast Genome-Wide Third-order SNP Interaction Tests with Information Gain on a Low-cost Heterogeneous Parallel FPGA-GPU Computing Architecture

Abstract Complex diseases may result from many genetic variants interacting with each other. For this reason, genome-wide interaction studies (GWIS) are currently performed to detect pairwise SNP interactions. While the computations required here can be completed within reasonable time, it has been inconvenient yet to detect third-order SNP interactions for large-scale datasets due to the cubic complexity of the problem. In this paper we introduce a feasible method for third-order GWIS analysis of genotyping data on a low-cost heterogeneous computing system that combines a Virtex-7 FPGA and a GeForce GTX 780 Ti GPU, with speedups between 70 and 90 against a CPU-only approach and a speedup of approx. 5 against a GPU-only approach. To estimate effect sizes of third-order interactions we employed information gain (IG), a measure that has been applied on a genome-wide scale only for pairwise interactions in the literature yet.

Combining GPU and FPGA technology for efficient exhaustive interaction analysis in GWAS

Interaction between genes has become a major topic in quantitative genetics. It is believed that these interactions play a significant role in genetic variations causing complex diseases. Due to the number of tests required for an exhaustive search in genome-wide association studies (GWAS), a large amount of computational power is required. In this paper, we present a hybrid architecture consisting of tightly interconnected CPUs, GPUs and FPGAs and a fine-tuned software suite to outperform other implementations in pairwise interaction analysis while consuming less than 300Watts and fitting into a standard desktop computer case.