China races to build record biobank to rival U.S. drugs research Biobanks store masses of biomedical data such as clinical records, genome sequences and other long-term health metrics that research and drug development depend on. As a fledgling researcher in U.S., Zhang Li was struck by the efficiency of extracting human tissue in the morning and mining it for data the same afternoon. Such a streamlined process had been missing from his years of training as a bio data scientist in China. Inspired, he returned home to Beijing to join the Chinese Institute for Brain Research and launch a national database that will collect blood and DNA samples from 33,000 children to help identify patterns of brain disease and their risk factors. "Biomedical data is extremely valuable and is fundamental for us to find solutions to diseases and to delay aging," said Zhang, surrounded by robotic arms carefully organizing blood samples.

Proteomics is the interdisciplinary field focusing on the large-scale study of proteins. Proteins essentially organize and execute all functions within organisms. Today, the bottom-up analysis approach is the most commonly used workflow, where proteins are digested into peptides and subsequently analyzed using Tandem Mass Spectrometry (MS/MS). MS-based proteomics has transformed various fields in life sciences, such as drug discovery and biomarker identification. Today, proteomics is entering a phase where it is helpful for clinical decision-making. Computational methods are vital in turning large amounts of acquired raw MS data into information and, ultimately, knowledge.

We consider the problem of projecting a vector onto the so-called k-capped simplex, which is a hyper-cube cut by a hyperplane. For an n-dimensional input vector with bounded elements, we found that a simple algorithm based on Newton's method is able to solve the projection problem to high precision with a complexity roughly about O(n), which has a much lower computational cost compared with the existing sorting-based methods proposed in the literature. We provide a theory for partial explanation and justification of the method. We demonstrate that the proposed algorithm can produce a solution of the projection problem with high precision on large scale datasets, and the algorithm is able to significantly outperform the state-of-the-art methods in terms of runtime (about 6-8 times faster than a commercial software with respect to CPU time for input vector with 1 million variables or more). We further illustrate the effectiveness of the proposed algorithm on solving sparse regression in a bioinformatics problem. Empirical results on the GWAS dataset (with 1,500,000 single-nucleotide polymorphisms) show that, when using the proposed method to accelerate the Projected Quasi-Newton (PQN) method, the accelerated PQN algorithm is able to handle huge-scale regression problem and it is more efficient (about 3-6 times faster) than the current state-of-the-art methods.

Understanding the consequences of mutation for molecular fitness and function is a fundamental problem in biology. Recently, generative probabilistic models have emerged as a powerful tool for estimating fitness from evolutionary sequence data, with accuracy sufficient to predict both laboratory measurements of function and disease risk in humans, and to design novel functional proteins. Existing techniques rest on an assumed relationship between density estimation and fitness estimation, a relationship that we interrogate in this article. We prove that fitness is not identifiable from observational sequence data alone, placing fundamental limits on our ability to disentangle fitness landscapes from phylogenetic history. We show on real datasets that perfect density estimation in the limit of infinite data would, with high confidence, result in poor fitness estimation; current models perform accurate fitness estimation because of, not despite, misspecification. Our results challenge the conventional wisdom that bigger models trained on bigger datasets will inevitably lead to better fitness estimation, and suggest novel estimation strategies going forward.

A.1 Access instructions OpenProteinSet is hosted by the Registry of Open Data on AWS (RODA) and can be accessed at the following link: registry.opendata.aws/openfold/. A.2 Documentation and intended uses We include a datasheet [1] in Section B. Detailed documentation on the precise structure and content of the dataset is provided on the dataset's landing page. A.3 Data format All OpenProteinSet files are in standard plaintext formats (A3M for MSAs, HHSearch format for template hits, and PDB for structure files) that can be read by a wide variety of bioinformatics software. A.5 License OpenProteinSet is made available under the CCBY 4.0 license. A copy of the license is provided with the dataset.

Multiple sequence alignments (MSAs) of proteins encode rich biological information and have been workhorses in bioinformatic methods for tasks like protein design and protein structure prediction for decades. Recent breakthroughs like AlphaFold2 that use transformers to attend directly over large quantities of raw MSAs have reaffirmed their importance. Generation of MSAs is highly computationally intensive, however, and no datasets comparable to those used to train AlphaFold2 have been made available to the research community, hindering progress in machine learning for proteins. To remedy this problem, we introduce OpenProteinSet, an open-source corpus of more than 16 million MSAs, associated structural homologs from the Protein Data Bank, and AlphaFold2 protein structure predictions. We have previously demonstrated the utility of OpenProteinSet by successfully retraining AlphaFold2 on it. We expect OpenProteinSet to be broadly useful as training and validation data for 1) diverse tasks focused on protein structure, function, and design and 2) large-scale multimodal machine learning research.

This article proposes a biconvex modification to convex biclustering in order to improve its performance in high-dimensional settings. In contrast to heuristics that discard a subset of noisy features a priori, our method jointly learns and accordingly weighs informative features while discovering biclusters. Moreover, the method is adaptive to the data, and is accompanied by an efficient algorithm based on proximal alternating minimization, complete with detailed guidance on hyperparameter tuning and efficient solutions to optimization subproblems. These contributions are theoretically grounded; we establish finite-sample bounds on the objective function under sub-Gaussian errors, and generalize these guarantees to cases where input affinities need not be uniform. Extensive simulation results reveal our method consistently recovers underlying biclusters while weighing and selecting features appropriately, outperforming peer methods. An application to a gene microarray dataset of lymphoma samples recovers biclusters matching an underlying classification, while giving additional interpretation to the mRNA samples via the column groupings and fitted weights.