{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:27:30Z","timestamp":1792787250091,"version":"4.5.0"},"reference-count":24,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100000805","name":"European Centre for Disease Prevention and Control","doi-asserted-by":"publisher","award":["ECDC\/GRANT\/2022\/010"],"award-info":[{"award-number":["ECDC\/GRANT\/2022\/010"]}],"id":[{"id":"10.13039\/501100000805","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Dutch Postcode Lottery, and the Dutch Ministry of Health, Welfare and Sports","award":["Dream Fund project \"No more pandemics\""],"award-info":[{"award-number":["Dream Fund project \"No more pandemics\""]}],"id":[{"id":"https:\/\/ror.org\/041evnj42","id-type":"ROR","asserted-by":"crossref"}]},{"name":"EPSRC","award":["EP\/Y018842\/1"],"award-info":[{"award-number":["EP\/Y018842\/1"]}],"id":[{"id":"https:\/\/ror.org\/0439y7842","id-type":"ROR","asserted-by":"crossref"}]},{"name":"MRC Centre for Global Infectious Disease Analysis","award":["MR\/R015600\/1"],"award-info":[{"award-number":["MR\/R015600\/1"]}]},{"name":"UKRI MRC","award":["MR\/X005895\/1"],"award-info":[{"award-number":["MR\/X005895\/1"]}]},{"name":"National Health Research Council Australia","award":["NHMRC, GNT2033803"],"award-info":[{"award-number":["NHMRC, GNT2033803"]}]},{"name":"NIH NIAID","award":["R01AI176401"],"award-info":[{"award-number":["R01AI176401"]}]},{"name":"StopTB Partnership","award":["STBP\/NT\/GSA\/2024-02"],"award-info":[{"award-number":["STBP\/NT\/GSA\/2024-02"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      The WHO mutation catalog is the reference for genotypic antimicrobial susceptibility predictions (ASPs) for\n                      <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                      . To increase sensitivity, WHO endorsed additional grading rules to classify mutations with insufficient experimental evidence. For rifampin, this includes any non-silent\n                      <jats:italic toggle=\"yes\">rpoB<\/jats:italic>\n                      mutation in the rifampin resistance-determining region (RRDR). For delamanid and pretomanid, the rules include loss-of-function (LoF) variants in six resistance genes, including\n                      <jats:italic toggle=\"yes\">fbiC<\/jats:italic>\n                      . Here, we describe three edge cases in which these additional grading rules overcalled resistance. The first case was a low-frequency\n                      <jats:italic toggle=\"yes\">rpoB<\/jats:italic>\n                      variant in RRDR caused by a sequencing artifact. The second case involved a tandem repeat region starting at the end of\n                      <jats:italic toggle=\"yes\">fbiC<\/jats:italic>\n                      . Because the H37Rv reference genome carries 2.7 repeats, deletion of one or two full repeats caused mapping errors, making these deletions appear as minority variants that trigger the\n                      <jats:italic toggle=\"yes\">fbiC<\/jats:italic>\n                      LoF rule. However, assembly showed that these deletions did not affect the\n                      <jats:italic toggle=\"yes\">fbiC<\/jats:italic>\n                      coding region because the remaining repeat substituted for the deleted repeats. The third case was a\n                      <jats:italic toggle=\"yes\">fbiC<\/jats:italic>\n                      frameshift in lineage 4.6.1 Uganda genotype strains, caused by a 19 bp duplication upstream of the same tandem repeat region. Although this frameshift affects the\n                      <jats:italic toggle=\"yes\">fbiC<\/jats:italic>\n                      coding region and meets the\n                      <jats:italic toggle=\"yes\">fbiC<\/jats:italic>\n                      LoF rule, sequence assembly revealed only a modest impact on the end of\n                      <jats:italic toggle=\"yes\">fbiC<\/jats:italic>\n                      . Although catalog performance remains high, WHO and others have acknowledged that, in specific situations, exceptions to its additional grading rules may result in unintended overcalling of resistance. Thus, systematic external quality control and communication of edge cases are essential.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Antimicrobial susceptibility predictions (ASPs) for\n                        <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                        using next-generation sequencing and the WHO mutation catalog are increasingly used for clinical decision-making. This avoids systematic false-resistant results of real-time PCR- or hybridization-based ASP assays caused by mutations that do not confer resistance (e.g., synonymous rifampin resistance-determining region [RRDR] mutations) and, potentially, subsequent inappropriate treatment adjustments. However, we demonstrate that false-resistant results occur even using the WHO mutation catalog for rifampin, delamanid, and pretomanid. Similar exceptions linked to the additional grading rules of the catalog are possible for other drugs, underlining the importance of monitoring the performance of the catalog continuously.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.01821-26","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T13:01:39Z","timestamp":1787749299000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Implications of edge cases for antimicrobial susceptibility predictions for rifampin, delamanid, and pretomanid with the WHO\n                    <i>Mycobacterium tuberculosis<\/i>\n                    mutation 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