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The Comprehensive Resistance Prediction for Tuberculosis: an International Consortium (CRyPTIC) presents here a data compendium of 12,289 Mycobacterium tuberculosis global clinical isolates, all of which have undergone whole-genome sequencing and have had their minimum inhibitory concentrations to 13 antitubercular drugs measured in a single assay. It is the largest matched phenotypic and genotypic dataset for M. tuberculosis to date. Here, we provide a summary detailing the breadth of data collected, along with a description of how the isolates were selected, collected, and uniformly processed in CRyPTIC partner laboratories across 23 countries. The compendium contains 6,814 isolates resistant to at least 1 drug, including 2,129 samples that fully satisfy the clinical definitions of rifampicin resistant (RR), multidrug resistant (MDR), pre-extensively drug resistant (pre-XDR), or extensively drug resistant (XDR). The data are enriched for rare resistance-associated variants, and the current limits of genotypic prediction of resistance status (sensitive/resistant) are presented by using a genetic mutation catalogue, along with the presence of suspected resistance-conferring mutations for isolates resistant to the newly introduced drugs bedaquiline, clofazimine, delamanid, and linezolid. Finally, a case study of rifampicin monoresistance demonstrates how this compendium could be used to advance our genetic understanding of rare resistance phenotypes. The data compendium is fully open source and it is hoped that it will facilitate and inspire future research for years to come.

Next generation sequencing (NGS) is a trending new standard for genotypic HIV-1 drug resistance (HIVDR) testing. Many NGS HIVDR data analysis pipelines have been independently developed, each with variable outputs and data management protocols. Standardization of such analytical methods and comparison of available pipelines are lacking, yet may impact subsequent HIVDR interpretation and other downstream applications. Here we compared the performance of five NGS HIVDR pipelines using proficiency panel samples from NIAID Virology Quality Assurance (VQA) program. Ten VQA panel specimens were genotyped by each of six international laboratories using their own in-house NGS assays. Raw NGS data were then processed using each of the five different pipelines including HyDRA, MiCall, PASeq, Hivmmer and DEEPGEN. All pipelines detected amino acid variants (AAVs) at full range of frequencies (1~100%) and demonstrated good linearity as compared to the reference frequency values. While the sensitivity in detecting low abundance AAVs, with frequencies between 1~20%, is less a concern for all pipelines, their specificity dramatically decreased at AAV frequencies <2%, suggesting that 2% threshold may be a more reliable reporting threshold for ensured specificity in AAV calling and reporting. More variations were observed among the pipelines when low abundance AAVs are concerned, likely due to differences in their NGS read quality control strategies. Findings from this study highlight the need for standardized strategies for NGS HIVDR data analysis, especially for the detection of minority HiVDR variants.Genotypic HIV drug resistance (HIVDR) testing not only guides effective clinical care of HIV-infected patients but also serves to provide surveillance of transmitted HIVDR in the population. Treatment guidelines in resource-permitted settings advocate the use of HIVDR monitoring both prior to ART initiation and when treatment failure is suspected 1,2 . There is increasing evidence showing that the presence of minority resistance variants open Scientific RepoRtS | (2020) 10:1634 | https://doi.org/10.1038/s41598-020-58544-z www.nature.com/scientificreports www.nature.com/scientificreports/ (MRV) in the HIV quasispecies (i.e., a swarm of highly-related but genotypically different viral variants) may be clinically significant and increase the risk of virological failure, impair immune recovery, lead to accumulation of drug resistance, increase risk of treatment switches and death [3][4][5][6][7][8] . A nationwide study in Mexico focusing on pretreatment drug resistance (PDR) found that lowering the detection threshold for PDR to 5% versus the conventional 20% improved the ability to identify patients with virological failure 6 . In addition, a European wide study found that pre-existing minority drug-resistant HIV-1 variants more than doubled the risk of virological failure to first-line NNRTI-based ART 9 . A more recent African study also reported similar findings, suggesting lowering the threshold below 20% improved the ability to i...