{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:49:49Z","timestamp":1790596189947,"version":"4.1.0"},"reference-count":65,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2017,11,1]],"date-time":"2017-11-01T00:00:00Z","timestamp":1509494400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Minority drug-resistant Mycobacterium tuberculosis subpopulations can be associated with phenotypic resistance but are poorly detected by Sanger sequencing or commercial molecular diagnostic assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To determine the role of targeted next-generation sequencing in resolving these minor variant subpopulations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used single molecule overlapping reads (SMOR), a targeted next-generation sequencing approach that dramatically reduces sequencing error, to analyze primary cultured isolates phenotypically resistant to rifampin, fluoroquinolones, or aminoglycosides, but for which Sanger sequencing found no resistance-associated variants (RAVs) within respective resistance-determining regions (study group). Isolates also underwent single-colony selection on antibiotic-containing agar, blinded to sequencing results. As a positive control, isolates with multiple colocalizing chromatogram peaks were also analyzed (control group).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>Among 61 primary culture isolates (25 study group and 36 control group), SMOR described 66 (49%) and 45 (33%) of 135 total heteroresistant RAVs at frequencies less than 5% and less than 1% of the total mycobacterial population, respectively. In the study group, SMOR detected minor resistant variant subpopulations in 80% (n\u2009=\u200920\/25) of isolates with no Sanger-identified RAVs (median subpopulation size, 1.0%; interquartile range, 0.2\u20133.9%). Single-colony selection on drug-containing media corroborated SMOR results for 90% (n\u2009=\u200918\/20) of RAV-containing specimens, and the absence of RAVs in 60% (n\u2009=\u20093\/5) of isolates. Overall, Sanger sequencing was concordant with SMOR for 77% (n\u2009=\u200953\/69) of macroheteroresistant (5\u201395% total population), but only 5% of microheteroresistant (&amp;lt;5%) subpopulations (n\u2009=\u20093\/66) across both groups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Cryptic minor variant mycobacterial subpopulations exist below the resolving capability of current drug susceptibility testing methodologies, and may explain an important proportion of false-negative resistance determinations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201703-0556oc","type":"journal-article","created":{"date-parts":[[2017,6,14]],"date-time":"2017-06-14T17:02:47Z","timestamp":1497459767000},"page":"1191-1201","source":"Crossref","is-referenced-by-count":48,"title":["Cryptic Microheteroresistance Explains\n                    <i>Mycobacterium 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