RawHash: Enabling Fast and Accurate Real-Time Analysis of Raw Nanopore Signals for Large Genomes

Nanopore sequencers generate electrical raw signals in real-time while sequencing long genomic strands. These raw signals can be analyzed as they are generated, providing an opportunity for real-time genome analysis. An important feature of nanopore sequencing, Read Until, can eject strands from sequencers without fully sequencing them, which provides opportunities to computationally reduce the sequencing time and cost. However, existing works utilizing Read Until either 1) require powerful computational resources that may not be available for portable sequencers or 2) lack scalability for large genomes, rendering them inaccurate or ineffective. We propose RawHash, the first mechanism that can accurately and efficiently perform real-time analysis of nanopore raw signals for large genomes using a hash-based similarity search. To enable this, RawHash ensures the signals corresponding to the same DNA content lead to the same hash value, regardless of the slight variations in these signals. RawHash achieves an accurate hash-based similarity search via an effective quantization of the raw signals such that signals corresponding to the same DNA content have the same quantized value and, subsequently, the same hash value. We evaluate RawHash on three applications: 1) read mapping, 2) relative abundance estimation, and 3) contamination analysis. Our evaluations show that RawHash is the only tool that can provide high accuracy and high throughput for analyzing large genomes in real-time. When compared to the state-of-the-art techniques, UNCALLED and Sigmap, RawHash provides 1) 25.8x and 3.4x better average throughput and 2) an average speedup of 32.1x and 2.1x in the mapping time, respectively. Source code is available at https://github.com/CMU-SAFARI/RawHash

A Framework for Designing Efficient Deep Learning-Based Genomic Basecallers

Nanopore sequencing generates noisy electrical signals that need to be converted into a standard string of DNA nucleotide bases using a computational step called basecalling. The accuracy and speed of basecalling have critical implications for all later steps in genome analysis. Many researchers adopt complex deep learning-based models to perform basecalling without considering the compute demands of such models, which leads to slow, inefficient, and memory-hungry basecallers. Therefore, there is a need to reduce the computation and memory cost of basecalling while maintaining accuracy. Our goal is to develop a comprehensive framework for creating deep learning-based basecallers that provide high efficiency and performance. We introduce RUBICON, a framework to develop hardware-optimized basecallers. RUBICON consists of two novel machine-learning techniques that are specifically designed for basecalling. First, we introduce the first quantization-aware basecalling neural architecture search (QABAS) framework to specialize the basecalling neural network architecture for a given hardware acceleration platform while jointly exploring and finding the best bit-width precision for each neural network layer. Second, we develop SkipClip, the first technique to remove the skip connections present in modern basecallers to greatly reduce resource and storage requirements without any loss in basecalling accuracy. We demonstrate the benefits of RUBICON by developing RUBICALL, the first hardware-optimized basecaller that performs fast and accurate basecalling. Compared to the fastest state-of-the-art basecaller, RUBICALL provides a 3.96x speedup with 2.97% higher accuracy. We show that RUBICON helps researchers develop hardware-optimized basecallers that are superior to expert-designed models

TargetCall: Eliminating the Wasted Computation in Basecalling via Pre-Basecalling Filtering

Basecalling is an essential step in nanopore sequencing analysis where the raw signals of nanopore sequencers are converted into nucleotide sequences, i.e., reads. State-of-the-art basecallers employ complex deep learning models to achieve high basecalling accuracy. This makes basecalling computationally-inefficient and memory-hungry; bottlenecking the entire genome analysis pipeline. However, for many applications, the majority of reads do no match the reference genome of interest (i.e., target reference) and thus are discarded in later steps in the genomics pipeline, wasting the basecalling computation. To overcome this issue, we propose TargetCall, the first fast and widely-applicable pre-basecalling filter to eliminate the wasted computation in basecalling. TargetCall's key idea is to discard reads that will not match the target reference (i.e., off-target reads) prior to basecalling. TargetCall consists of two main components: (1) LightCall, a lightweight neural network basecaller that produces noisy reads; and (2) Similarity Check, which labels each of these noisy reads as on-target or off-target by matching them to the target reference. TargetCall filters out all off-target reads before basecalling; and the highly-accurate but slow basecalling is performed only on the raw signals whose noisy reads are labeled as on-target. Our thorough experimental evaluations using both real and simulated data show that TargetCall 1) improves the end-to-end basecalling performance of the state-of-the-art basecaller by 3.31x while maintaining high (98.88%) sensitivity in keeping on-target reads, 2) maintains high accuracy in downstream analysis, 3) precisely filters out up to 94.71% of off-target reads, and 4) achieves better performance, sensitivity, and generality compared to prior works. We freely open-source TargetCall at https://github.com/CMU-SAFARI/TargetCall

RowPress: Amplifying Read Disturbance in Modern DRAM Chips

Memory isolation is critical for system reliability, security, and safety. Unfortunately, read disturbance can break memory isolation in modern DRAM chips. For example, RowHammer is a well-studied read-disturb phenomenon where repeatedly opening and closing (i.e., hammering) a DRAM row many times causes bitflips in physically nearby rows. This paper experimentally demonstrates and analyzes another widespread read-disturb phenomenon, RowPress, in real DDR4 DRAM chips. RowPress breaks memory isolation by keeping a DRAM row open for a long period of time, which disturbs physically nearby rows enough to cause bitflips. We show that RowPress amplifies DRAM's vulnerability to read-disturb attacks by significantly reducing the number of row activations needed to induce a bitflip by one to two orders of magnitude under realistic conditions. In extreme cases, RowPress induces bitflips in a DRAM row when an adjacent row is activated only once. Our detailed characterization of 164 real DDR4 DRAM chips shows that RowPress 1) affects chips from all three major DRAM manufacturers, 2) gets worse as DRAM technology scales down to smaller node sizes, and 3) affects a different set of DRAM cells from RowHammer and behaves differently from RowHammer as temperature and access pattern changes. We demonstrate in a real DDR4-based system with RowHammer protection that 1) a user-level program induces bitflips by leveraging RowPress while conventional RowHammer cannot do so, and 2) a memory controller that adaptively keeps the DRAM row open for a longer period of time based on access pattern can facilitate RowPress-based attacks. To prevent bitflips due to RowPress, we describe and evaluate a new methodology that adapts existing RowHammer mitigation techniques to also mitigate RowPress with low additional performance overhead. We open source all our code and data to facilitate future research on RowPress.Comment: Extended version of the paper "RowPress: Amplifying Read Disturbance in Modern DRAM Chips" at the 50th Annual International Symposium on Computer Architecture (ISCA), 202

ApHMM: Accelerating Profile Hidden Markov Models for Fast and Energy-Efficient Genome Analysis

Profile hidden Markov models (pHMMs) are widely employed in various bioinformatics applications to identify similarities between biological sequences, such as DNA or protein sequences. In pHMMs, sequences are represented as graph structures. These probabilities are subsequently used to compute the similarity score between a sequence and a pHMM graph. The Baum-Welch algorithm, a prevalent and highly accurate method, utilizes these probabilities to optimize and compute similarity scores. However, the Baum-Welch algorithm is computationally intensive, and existing solutions offer either software-only or hardware-only approaches with fixed pHMM designs. We identify an urgent need for a flexible, high-performance, and energy-efficient HW/SW co-design to address the major inefficiencies in the Baum-Welch algorithm for pHMMs. We introduce ApHMM, the first flexible acceleration framework designed to significantly reduce both computational and energy overheads associated with the Baum-Welch algorithm for pHMMs. ApHMM tackles the major inefficiencies in the Baum-Welch algorithm by 1) designing flexible hardware to accommodate various pHMM designs, 2) exploiting predictable data dependency patterns through on-chip memory with memoization techniques, 3) rapidly filtering out negligible computations using a hardware-based filter, and 4) minimizing redundant computations. ApHMM achieves substantial speedups of 15.55x - 260.03x, 1.83x - 5.34x, and 27.97x when compared to CPU, GPU, and FPGA implementations of the Baum-Welch algorithm, respectively. ApHMM outperforms state-of-the-art CPU implementations in three key bioinformatics applications: 1) error correction, 2) protein family search, and 3) multiple sequence alignment, by 1.29x - 59.94x, 1.03x - 1.75x, and 1.03x - 1.95x, respectively, while improving their energy efficiency by 64.24x - 115.46x, 1.75x, 1.96x.Comment: Accepted to ACM TAC

Mimar Sinan Dergisi

Ankara : İhsan Doğramacı Bilkent Üniversitesi İktisadi, İdari ve Sosyal Bilimler Fakültesi, Tarih Bölümü, 2018.This work is a student project of the Department of History, Faculty of Economics, Administrative and Social Sciences, İhsan Doğramacı Bilkent University.The History of Turkey course (HIST200) is a requirement for all Bilkent undergraduates. It is designed to encourage students to work in groups on projects concerning any topic of their choice that relates to the history of Turkey. It is designed as an interactive course with an emphasis on research and the objective of investigating events, chronologically short historical periods, as well as historic representations. Students from all departments prepare and present final projects for examination by a committee, with 10 projects chosen to receive awards.Includes bibliographical references (page 15).by Süha Ünsal

AirLift: A Fast and Comprehensive Technique for Remapping Alignments between Reference Genomes

As genome sequencing tools and techniques improve, researchers are able to incrementally assemble more accurate reference genomes, which enable sensitivity in read mapping and downstream analysis such as variant calling. A more sensitive downstream analysis is critical for a better understanding of the genome donor (e.g., health characteristics). Therefore, read sets from sequenced samples should ideally be mapped to the latest available reference genome that represents the most relevant population. Unfortunately, the increasingly large amount of available genomic data makes it prohibitively expensive to fully re-map each read set to its respective reference genome every time the reference is updated. There are several tools that attempt to accelerate the process of updating a read data set from one reference to another (i.e., remapping). However, if a read maps to a region in the old reference that does not appear with a reasonable degree of similarity in the new reference, the read cannot be remapped. We find that, as a result of this drawback, a significant portion of annotations are lost when using state-of-the-art remapping tools. To address this major limitation in existing tools, we propose AirLift, a fast and comprehensive technique for remapping alignments from one genome to another. Compared to the state-of-the-art method for remapping reads (i.e., full mapping), AirLift reduces 1) the number of reads that need to be fully mapped to the new reference by up to 99.99\% and 2) the overall execution time to remap read sets between two reference genome versions by 6.7x, 6.6x, and 2.8x for large (human), medium (C. elegans), and small (yeast) reference genomes, respectively. We validate our remapping results with GATK and find that AirLift provides similar accuracy in identifying ground truth SNP and INDEL variants as the baseline of fully mapping a read set

ApHMM: Accelerating Profile Hidden Markov Models for Fast and Energy-Efficient Genome Analysis

Profile hidden Markov models (pHMMs) are widely used in many bioinformatics applications to accurately identify similarities between biological sequences (e.g., DNA or protein sequences). PHMMs use a commonly-adopted and highly-accurate method, called the Baum-Welch algorithm, to calculate these similarities. However, the Baum-Welch algorithm is computationally expensive, and existing works provide either software- or hardware-only solutions for a fixed pHMM design. When we analyze the state-of-the-art works, we find that there is a pressing need for a flexible, high-performant, and energy-efficient hardware-software co-design to efficiently and effectively solve all the major inefficiencies in the Baum-Welch algorithm for pHMMs. We propose ApHMM, the first flexible acceleration framework that can significantly reduce computational and energy overheads of the Baum-Welch algorithm for pHMMs. ApHMM leverages hardware-software co-design to solve the major inefficiencies in the Baum-Welch algorithm by 1) designing a flexible hardware to support different pHMMs designs, 2) exploiting the predictable data dependency pattern in an on-chip memory with memoization techniques, 3) quickly eliminating negligible computations with a hardware-based filter, and 4) minimizing the redundant computations. We implement our 1) hardware-software optimizations on a specialized hardware and 2) software optimizations for GPUs to provide the first flexible Baum-Welch accelerator for pHMMs. ApHMM provides significant speedups of 15.55x-260.03x, 1.83x-5.34x, and 27.97x compared to CPU, GPU, and FPGA implementations of the Baum-Welch algorithm, respectively. ApHMM outperforms the state-of-the-art CPU implementations of three important bioinformatics applications, 1) error correction, 2) protein family search, and 3) multiple sequence alignment, by 1.29x-59.94x, 1.03x-1.75x, and 1.03x-1.95x, respectively