In single-cell perturbation prediction, a central task is to forecast the effects of perturbing a gene unseen in the training data. The efficacy of such predictions depends on two factors: (1) the similarity of the target gene to those covered in the training data, which informs model (epistemic) uncertainty, and (2) the quality of the corresponding training data, which reflects data (aleatoric) uncertainty. Both factors are critical for determining the reliability of a prediction, particularly as gene perturbation is an inherently stochastic biochemical process. In this paper, we propose PRESCRIBE (PREdicting Single-Cell Response wIth Bayesian Estimation), a multivariate deep evidential regression framework designed to measure both sources of uncertainty jointly. Our analysis demonstrates that PRESCRIBE effectively estimates a confidence score for each prediction, which strongly correlates with its empirical accuracy. This capability enables the filtering of untrustworthy results, and in our experiments, it achieves steady accuracy improvements of over 3% compared to comparable baselines.

Abstract Mutually exclusive gene expression, where gene pairs are expressed in strict alternation within individual cells, reflects fundamental inter-gene regulatory mechanisms and can reveal shifts in transcriptional programs during development or disease. Detecting such patterns is critical for resolving rare cellular subpopulations, temporally discrete states along pseudotime, and spatially segregated neighborhoods in single-cell and spatial multi-omics data. However, the sparsity and dropout inherent to single-cell data make mutually exclusive expression difficult to detect, leading conventional feature selection methods to overlook subtle yet functionally important genes. We present MULE, an unbiased framework that systematically organizes collective mutual exclusivity into a hierarchical taxonomy. Applying MULE to cardiac datasets, we uncovered robust upregulation of SPOCK1 and SLC6A6 in dilated cardiomyopathy, previously obscured by the inability to resolve pathological cardiomyocytes. In vivo and in vitro experiments demonstrated that stress-induced SLC6A6 upregulation serves a cardiomyocyte self-protective mechanism. Taurine supplementation reduced oxidative stress, restored calcium homeostasis, prevented cell death, and improved cardiac function post-injury. These findings elucidate a novel cardiomyocyte stress response and highlight the therapeutic promise of taurine supplementation for the treatment of dilated cardiomyopathy.

Abstract Single-cell and spatial transcriptomics enable high-resolution characterization of cellular states, but standard analyses often rely on Euclidean or log-transformed distances that distort cell-to-cell relationships. Euclidean distances on normalized counts overemphasize highly expressed genes, while log transformations amplify qualitative on/off differences and are sensitive to sequencing depth. To overcome these limitations, we introduce GAIA (Geometric Analysis from an Information Aspect), an information-geometric framework that models each cell as a multinomial distribution over genes. Distances between cells are measured using the Fisher-Rao metric, which reduces to angular distances on a unit hypersphere after a square-root transformation. This geodesic approach provides a principled, interpretable, and computationally efficient similarity measure. GAIA naturally reconciles qualitative and quantitative gene expression variation: subtle quantitative changes correspond to smooth displacements along the manifold, while qualitative transitions induce larger geodesic separations. It preserves robust and consistent cell-to-cell relationships, mitigates sequencing-depth effects and reduces the need for labor-intensive gene selection. In spatial transcriptomics, GAIA amplifies nuanced transcriptomic differences between spots, improving domain segmentation. Overall, GAIA offers a knowledge-lean, variance-stabilizing framework for analyzing single-cell and spatial transcriptomic data, enhancing the resolution of cell type and state identification.

Few-shot classification aims to learn a classifier that categorizes objects of unseen classes with limited samples. One general approach is to mine as much information as possible from limited samples. This can be achieved by incorporating data from multiple modalities. However, existing multi-modality methods only use additional modality in support samples while adhering to a single modal in query samples. Such approach could lead to information imbalance between support and query samples, which confounds model generalization from support to query samples. Towards this problem, we propose a task-adaptive semantic feature learning mechanism to incorporate semantic features for both support and query samples. The semantic feature learner is trained episodic-wisely by regressing from the feature vectors of the support samples. It is utilized to predict semantic features for the query samples. Such method maintains a consistent training scheme between support and query samples and enables direct model transfer from support to query data, which significantly improves model generalization. We conduct extensive experiments on four benchmarks in both inductive and transductive settings. Results show that the proposed TasNet outperforms state-of-the-art methods with an improvement of 1% to 5% in classification accuracy , demonstrating the superiority of our method. The exhaustive ablation studies further validate the effectiveness of our framework. The code is available at: https://github.com/pmhDL/TasNet

Due to the shortage of COVID-19 viral testing kits, radiology imaging is used to complement the screening process. Deep learning based methods are promising in automatically detecting COVID-19 disease in chest x-ray images. Most of these works first train a Convolutional Neural Network (CNN) on an existing large-scale chest x-ray image dataset and then fine-tune the model on the newly collected COVID-19 chest x-ray dataset, often at a much smaller scale. However, simple fine-tuning may lead to poor performance for the CNN model due to two issues, first the large domain shift present in chest x-ray datasets and second the relatively small scale of the COVID-19 chest x-ray dataset. In an attempt to address these two important issues, we formulate the problem of COVID-19 chest x-ray image classification in a semi-supervised open set domain adaptation setting and propose a novel domain adaptation method, Semi-supervised Open set Domain Adversarial network (SODA). SODA is designed to align the data distributions across different domains in the general domain space and also in the common subspace of source and target data. In our experiments, SODA achieves a leading classification performance compared with recent state-of-the-art models in separating COVID-19 with common pneumonia. We also present initial results showing that SODA can produce better pathology localizations in the chest x-rays.

MOTIVATION: Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq), couples the measurement of surface marker proteins with simultaneous sequencing of mRNA at single cell level, which brings accurate cell surface phenotyping to single-cell transcriptomics. Unfortunately, multiplets in CITE-seq datasets create artificial cell types (ACT) and complicate the automation of cell surface phenotyping. RESULTS: We propose CITE-sort, an artificial-cell-type aware surface marker clustering method for CITE-seq. CITE-sort is aware of and is robust to multiplet-induced ACT. We benchmarked CITE-sort with real and simulated CITE-seq datasets and compared CITE-sort against canonical clustering methods. We show that CITE-sort produces the best clustering performance across the board. CITE-sort not only accurately identifies real biological cell types (BCT) but also consistently and reliably separates multiplet-induced artificial-cell-type droplet clusters from real BCT droplet clusters. In addition, CITE-sort organizes its clustering process with a binary tree, which facilitates easy interpretation and verification of its clustering result and simplifies cell-type annotation with domain knowledge in CITE-seq. AVAILABILITY AND IMPLEMENTATION: http://github.com/QiuyuLian/CITE-sort. SUPPLEMENTARY INFORMATION: Supplementary data is available at Bioinformatics online.

Motivation: Most modern seed-and-extend NGS read mappers employ a seeding scheme that requires extracting t non-overlapping seeds in each read in order to find all valid mappings under an edit distance threshold of t. As t grows (such as in long reads with high error rate), this seeding scheme forces mappers to use more and shorter seeds, which increases the seed hits (seed frequencies) and therefore reduces the efficiency of mappers. Results: We propose a novel seeding framework, context-aware seeds (CAS). CAS guarantees finding all valid mapping but uses fewer (and longer) seeds, which reduces seed frequencies and increases efficiency of mappers. CAS achieves this improvement by attaching a confidence radius to each seed in the reference. We prove that all valid mappings can be found if the sum of confidence radii of seeds are greater than t. CAS generalizes the existing pigeonhole-principle-based seeding scheme in which this confidence radius is implicitly always 1. Moreover, we design an efficient algorithm that constructs the confidence radius database in linear time. We experiment CAS with E. coli genome and show that CAS reduces seed frequencies by up to 20.3% when compared with the state-of-the-art pigeonhole-principle-based seeding algorithm, the Optimal Seed Solver. Availability: https://github.com/Kingsford-Group/CAS_code

MOTIVATION: High throughput DNA sequencing (HTS) technologies generate an excessive number of small DNA segments -called short reads- that cause significant computational burden. To analyze the entire genome, each of the billions of short reads must be mapped to a reference genome based on the similarity between a read and 'candidate' locations in that reference genome. The similarity measurement, called alignment, formulated as an approximate string matching problem, is the computational bottleneck because: (i) it is implemented using quadratic-time dynamic programming algorithms and (ii) the majority of candidate locations in the reference genome do not align with a given read due to high dissimilarity. Calculating the alignment of such incorrect candidate locations consumes an overwhelming majority of a modern read mapper's execution time. Therefore, it is crucial to develop a fast and effective filter that can detect incorrect candidate locations and eliminate them before invoking computationally costly alignment algorithms. RESULTS: We propose GateKeeper, a new hardware accelerator that functions as a pre-alignment step that quickly filters out most incorrect candidate locations. GateKeeper is the first design to accelerate pre-alignment using Field-Programmable Gate Arrays (FPGAs), which can perform pre-alignment much faster than software. When implemented on a single FPGA chip, GateKeeper maintains high accuracy (on average >96%) while providing, on average, 90-fold and 130-fold speedup over the state-of-the-art software pre-alignment techniques, Adjacency Filter and Shifted Hamming Distance (SHD), respectively. The addition of GateKeeper as a pre-alignment step can reduce the verification time of the mrFAST mapper by a factor of 10. AVAILABILITY AND IMPLEMENTATION: https://github.com/BilkentCompGen/GateKeeper. CONTACT: [email protected] or [email protected] or [email protected]. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Optimizing seed selection is an important problem in read mapping. The number of non-overlapping seeds a mapper selects determines the sensitivity of the mapper while the total frequency of all selected seeds determines the speed of the mapper. Modern seed-and-extend mappers usually select seeds with either an equal and fixed-length scheme or with an inflexible placement scheme, both of which limit the ability of the mapper in selecting less frequent seeds to speed up the mapping process. Therefore, it is crucial to develop a new algorithm that can adjust both the individual seed length and the seed placement, as well as derive less frequent seeds. RESULTS: We present the Optimal Seed Solver (OSS), a dynamic programming algorithm that discovers the least frequently-occurring set of x seeds in an L-base-pair read in [Formula: see text] operations on average and in [Formula: see text] operations in the worst case, while generating a maximum of [Formula: see text] seed frequency database lookups. We compare OSS against four state-of-the-art seed selection schemes and observe that OSS provides a 3-fold reduction in average seed frequency over the best previous seed selection optimizations. AVAILABILITY AND IMPLEMENTATION: We provide an implementation of the Optimal Seed Solver in C++ at: https://github.com/CMU-SAFARI/Optimal-Seed-Solver CONTACT: [email protected], [email protected] or [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Abstract Motivation: Calculating the edit-distance (i.e. minimum number of insertions, deletions and substitutions) between short DNA sequences is the primary task performed by seed-and-extend based mappers, which compare billions of sequences. In practice, only sequence pairs with a small edit-distance provide useful scientific data. However, the majority of sequence pairs analyzed by seed-and-extend based mappers differ by significantly more errors than what is typically allowed. Such error-abundant sequence pairs needlessly waste resources and severely hinder the performance of read mappers. Therefore, it is crucial to develop a fast and accurate filter that can rapidly and efficiently detect error-abundant string pairs and remove them from consideration before more computationally expensive methods are used. Results: We present a simple and efficient algorithm, Shifted Hamming Distance (SHD), which accelerates the alignment verification procedure in read mapping, by quickly filtering out error-abundant sequence pairs using bit-parallel and SIMD-parallel operations. SHD only filters string pairs that contain more errors than a user-defined threshold, making it fully comprehensive. It also maintains high accuracy with moderate error threshold (up to 5% of the string length) while achieving a 3-fold speedup over the best previous algorithm (Gene Myers’s bit-vector algorithm). SHD is compatible with all mappers that perform sequence alignment for verification. Availability and implementation: We provide an implementation of SHD in C with Intel SSE instructions at: https://github.com/CMU-SAFARI/SHD. Contact: [email protected], [email protected] or [email protected] Supplementary information: Supplementary data are available at Bioinformatics online.

Many modern high-performance processors prefetch blocks into the on-chip cache. Prefetched blocks can potentially pollute the cache by evicting more useful blocks. In this work, we observe that both accurate and inaccurate prefetches lead to cache pollution, and propose a comprehensive mechanism to mitigate prefetcher-caused cache pollution. First, we observe that over 95% of useful prefetches in a wide variety of applications are not reused after the first demand hit (in secondary caches). Based on this observation, our first mechanism simply demotes a prefetched block to the lowest priority on a demand hit. Second, to address pollution caused by inaccurate prefetches, we propose a self-tuning prefetch accuracy predictor to predict if a prefetch is accurate or inaccurate. Only predicted-accurate prefetches are inserted into the cache with a high priority. Evaluations show that our final mechanism, which combines these two ideas, significantly improves performance compared to both the baseline LRU policy and two state-of-the-art approaches to mitigating prefetcher-caused cache pollution (up to 49%, and 6% on average for 157 two-core multiprogrammed workloads). The performance improvement is consistent across a wide variety of system configurations.

Compute-intensive applications are emerging in intelligent home, retail store and automotive industries. These applications are becoming more sophisticated with new features rich in audio, video, image, and machine learning capabilities that demand heavy computations. We present the EMERALD (EMERging Applications and algorithms for Low power Device) workload suite. We profile the workloads to show the hotspot functions that are candidates for hardware accelerators.

Data compression is a promising approach for meeting the increasing memory capacity demands expected in future systems. Unfortunately, existing compression algorithms do not translate well when directly applied to main memory because they require the memory controller to perform non-trivial computation to locate a cache line within a compressed memory page, thereby increasing access latency and degrading system performance. Prior proposals for addressing this performance degradation problem are either costly or energy inefficient.

Numerous tools have been proposed to help developers fix software errors and inefficiencies. Widely-used techniques such as memory checking suffer from overheads that limit their use to pre-deployment testing, while more advanced systems have such severe performance impacts that they may require special-purpose hardware. Previous works have described hardware that can accelerate individual analyses, but such specialization stymies adoption; generalized mechanisms are more likely to be added to commercial processors. This paper demonstrates that the ability to set an unlimited number of fine-grain data watchpoints can reduce the runtime overheads of numerous dynamic software analysis techniques. We detail the watchpoint capabilities required to accelerate these analyses while remaining general enough to be useful in the future. We describe a hardware design that stores watchpoints in main memory and utilizes two different on-chip caches to accelerate performance. The first is a bitmap lookaside buffer that stores fine-grained watchpoints, while the second is a range cache that can efficiently hold large contiguous regions of watchpoints. As an example of the power of such a system, it is possible to use watchpoints to accelerate read/write set checks in a software data race detector by nearly 9x.