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1. METABOLIC: high-throughput profiling of microbial genomes for functional traits, metabolism, biogeochemistry, and community-scale functional networks

   https://doi.org/10.1186/s40168-021-01213-8  

   Zhou, Zhichao ; Tran, Patricia Q. ; Breister, Adam M. ; Liu, Yang ; Kieft, Kristopher ; Cowley, Elise S. ; Karaoz, Ulas ; Anantharaman, Karthik ( February 2022 , Microbiome)

   Advances in microbiome science are being driven in large part due to our ability to study and infer microbial ecology from genomes reconstructed from mixed microbial communities using metagenomics and single-cell genomics. Such omics-based techniques allow us to read genomic blueprints of microorganisms, decipher their functional capacities and activities, and reconstruct their roles in biogeochemical processes. Currently available tools for analyses of genomic data can annotate and depict metabolic functions to some extent; however, no standardized approaches are currently available for the comprehensive characterization of metabolic predictions, metabolite exchanges, microbial interactions, and microbial contributions to biogeochemical cycling.

   We present METABOLIC (METabolic And BiogeOchemistry anaLyses In miCrobes), a scalable software to advance microbial ecology and biogeochemistry studies using genomes at the resolution of individual organisms and/or microbial communities. The genome-scale workflow includes annotation of microbial genomes, motif validation of biochemically validated conserved protein residues, metabolic pathway analyses, and calculation of contributions to individual biogeochemical transformations and cycles. The community-scale workflow supplements genome-scale analyses with determination of genome abundance in the microbiome, potential microbial metabolic handoffs and metabolite exchange, reconstruction of functional networks, and determination of microbial contributions to biogeochemical cycles. METABOLIC can take input genomes from isolates, metagenome-assembled genomes, or single-cell genomes. Results are presented in the form of tables for metabolism and a variety of visualizations including biogeochemical cycling potential, representation of sequential metabolic transformations, community-scale microbial functional networks using a newly defined metric “MW-score” (metabolic weight score), and metabolic Sankey diagrams. METABOLIC takes ~ 3 h with 40 CPU threads to process ~ 100 genomes and corresponding metagenomic reads within which the most compute-demanding part of hmmsearch takes ~ 45 min, while it takes ~ 5 h to complete hmmsearch for ~ 3600 genomes. Tests of accuracy, robustness, and consistency suggest METABOLIC provides better performance compared to other software and online servers. To highlight the utility and versatility of METABOLIC, we demonstrate its capabilities on diverse metagenomic datasets from the marine subsurface, terrestrial subsurface, meadow soil, deep sea, freshwater lakes, wastewater, and the human gut.

   METABOLIC enables the consistent and reproducible study of microbial community ecology and biogeochemistry using a foundation of genome-informed microbial metabolism, and will advance the integration of uncultivated organisms into metabolic and biogeochemical models. METABOLIC is written in Perl and R and is freely available under GPLv3 athttps://github.com/AnantharamanLab/METABOLIC.

    

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2. FireSim: FPGA-Accelerated Cycle-Exact Scale-Out System Simulation in the Public Cloud

   https://doi.org/10.1109/ISCA.2018.00014  

   Karandikar, Sagar ; Mao, Howard ; Kim, Donggyu ; Biancolin, David ; Amid, Alon ; Lee, Dayeol ; Pemberton, Nathan ; Amaro, Emmanuel ; Schmidt, Colin ; Chopra, Aditya ; et al ( June 2018 , 2018 ACM/IEEE 45th Annual International Symposium on Computer Architecture (ISCA))

   We present FireSim, an open-source simulation platform that enables cycle-exact microarchitectural simulation of large scale-out clusters by combining FPGA-accelerated simulation of silicon-proven RTL designs with a scalable, distributed network simulation. Unlike prior FPGA-accelerated simulation tools, FireSim runs on Amazon EC2 F1, a public cloud FPGA platform, which greatly improves usability, provides elasticity, and lowers the cost of large-scale FPGA-based experiments. We describe the design and implementation of FireSim and show how it can provide sufficient performance to run modern applications at scale, to enable true hardware-software co-design. As an example, we demonstrate automatically generating and deploying a target cluster of 1,024 3.2 GHz quad-core server nodes, each with 16 GB of DRAM, interconnected by a 200 Gbit/s network with 2 microsecond latency, which simulates at a 3.4 MHz processor clock rate (less than 1,000x slowdown over real-time). In aggregate, this FireSim instantiation simulates 4,096 cores and 16 TB of memory, runs ~ 14 billion instructions per second, and harnesses 12.8 million dollars worth of FPGAs-at a total cost of only ~ $100 per simulation hour to the user. We present several examples to show how FireSim can be used to explore various research directions in warehouse-scale machine design, including modeling networks with high-bandwidth and low-latency, integrating arbitrary RTL designs for a variety of commodity and specialized datacenter nodes, and modeling a variety of datacenter organizations, as well as reusing the scale-out FireSim infrastructure to enable fast, massively parallel cycle-exact single-node microarchitectural experimentation. 

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3. A weighted exact test for mutually exclusive mutations in cancer

   https://doi.org/10.1093/bioinformatics/btw462  

   Leiserson, Mark DM ; Reyna, Matthew A. ; Raphael, Benjamin J. ( August 2016 , Bioinformatics)

   The somatic mutations in the pathways that drive cancer development tend to be mutually exclusive across tumors, providing a signal for distinguishing driver mutations from a larger number of random passenger mutations. This mutual exclusivity signal can be confounded by high and highly variable mutation rates across a cohort of samples. Current statistical tests for exclusivity that incorporate both per-gene and per-sample mutational frequencies are computationally expensive and have limited precision.

   We formulate a weighted exact test for assessing the significance of mutual exclusivity in an arbitrary number of mutational events. Our test conditions on the number of samples with a mutation as well as per-event, per-sample mutation probabilities. We provide a recursive formula to compute P-values for the weighted test exactly as well as a highly accurate and efficient saddlepoint approximation of the test. We use our test to approximate a commonly used permutation test for exclusivity that conditions on per-event, per-sample mutation frequencies. However, our test is more efficient and it recovers more significant results than the permutation test. We use our Weighted Exclusivity Test (WExT) software to analyze hundreds of colorectal and endometrial samples from The Cancer Genome Atlas, which are two cancer types that often have extremely high mutation rates. On both cancer types, the weighted test identifies sets of mutually exclusive mutations in cancer genes with fewer false positives than earlier approaches.

   See http://compbio.cs.brown.edu/projects/wext for software.

   braphael@cs.brown.edu

   Supplementary data are available at Bioinformatics online.

    

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4. A list-mode multi-energy window low-count SPECT reconstruction method for isotopes with multiple emission peaks

   https://doi.org/10.1186/s40658-023-00558-3  

   Rahman, Md Ashequr ; Li, Zekun ; Yu, Zitong ; Laforest, Richard ; Thorek, Daniel L. J. ; Jha, Abhinav K. ( June 2023 , EJNMMI Physics)

   Single-photon emission computed tomography (SPECT) provides a mechanism to perform absorbed-dose quantification tasks for$$\alpha$$$\alpha$-particle radiopharmaceutical therapies ($$\alpha$$$\alpha$-RPTs). However, quantitative SPECT for$$\alpha$$$\alpha$-RPT is challenging due to the low number of detected counts, the complex emission spectrum, and other image-degrading artifacts. Towards addressing these challenges, we propose a low-count quantitative SPECT reconstruction method for isotopes with multiple emission peaks.

   Given the low-count setting, it is important that the reconstruction method extracts the maximal possible information from each detected photon. Processing data over multiple energy windows and in list-mode (LM) format provide mechanisms to achieve that objective. Towards this goal, we propose a list-mode multi energy window (LM-MEW) ordered-subsets expectation–maximization-based SPECT reconstruction method that uses data from multiple energy windows in LM format and include the energy attribute of each detected photon. For computational efficiency, we developed a multi-GPU-based implementation of this method. The method was evaluated using 2-D SPECT simulation studies in a single-scatter setting conducted in the context of imaging [$$^{223}$$${}^{223}$Ra]RaCl$${_2}$$${}_2$, an FDA-approved RPT for metastatic prostate cancer.

   The proposed method yielded improved performance on the task of estimating activity uptake within known regions of interest in comparison to approaches that use a single energy window or use binned data. The improved performance was observed in terms of both accuracy and precision and for different sizes of the region of interest.

   Results of our studies show that the use of multiple energy windows and processing data in LM format with the proposed LM-MEW method led to improved quantification performance in low-count SPECT of isotopes with multiple emission peaks. These results motivate further development and validation of the LM-MEW method for such imaging applications, including for$$\alpha$$$\alpha$-RPT SPECT.

    

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5. Deep Learning Approaches to Surrogates for Solving the Diffusion Equation for Mechanistic Real-World Simulations

   https://doi.org/10.3389/fphys.2021.667828  

   Toledo-Marín, J. Quetzalcóatl ; Fox, Geoffrey ; Sluka, James P. ; Glazier, James A. ( June 2021 , Frontiers in Physiology)

   In many mechanistic medical, biological, physical, and engineered spatiotemporal dynamic models the numerical solution of partial differential equations (PDEs), especially for diffusion, fluid flow and mechanical relaxation, can make simulations impractically slow. Biological models of tissues and organs often require the simultaneous calculation of the spatial variation of concentration of dozens of diffusing chemical species. One clinical example where rapid calculation of a diffusing field is of use is the estimation of oxygen gradients in the retina, based on imaging of the retinal vasculature, to guide surgical interventions in diabetic retinopathy. Furthermore, the ability to predict blood perfusion and oxygenation may one day guide clinical interventions in diverse settings, i.e., from stent placement in treating heart disease to BOLD fMRI interpretation in evaluating cognitive function (Xie et al., 2019 ; Lee et al., 2020 ). Since the quasi-steady-state solutions required for fast-diffusing chemical species like oxygen are particularly computationally costly, we consider the use of a neural network to provide an approximate solution to the steady-state diffusion equation. Machine learning surrogates, neural networks trained to provide approximate solutions to such complicated numerical problems, can often provide speed-ups of several orders of magnitude compared to direct calculation. Surrogates of PDEs could enable use of larger and more detailed models than are possible with direct calculation and can make including such simulations in real-time or near-real time workflows practical. Creating a surrogate requires running the direct calculation tens of thousands of times to generate training data and then training the neural network, both of which are computationally expensive. Often the practical applications of such models require thousands to millions of replica simulations, for example for parameter identification and uncertainty quantification, each of which gains speed from surrogate use and rapidly recovers the up-front costs of surrogate generation. We use a Convolutional Neural Network to approximate the stationary solution to the diffusion equation in the case of two equal-diameter, circular, constant-value sources located at random positions in a two-dimensional square domain with absorbing boundary conditions. Such a configuration caricatures the chemical concentration field of a fast-diffusing species like oxygen in a tissue with two parallel blood vessels in a cross section perpendicular to the two blood vessels. To improve convergence during training, we apply a training approach that uses roll-back to reject stochastic changes to the network that increase the loss function. The trained neural network approximation is about 1000 times faster than the direct calculation for individual replicas. Because different applications will have different criteria for acceptable approximation accuracy, we discuss a variety of loss functions and accuracy estimators that can help select the best network for a particular application. We briefly discuss some of the issues we encountered with overfitting, mismapping of the field values and the geometrical conditions that lead to large absolute and relative errors in the approximate solution. 

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