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We introduce sylph, a species-level metagenome profiler that estimates genome-to-metagenome containment average nucleotide identity (ANI) through zero-inflated Poisson\n                    <jats:italic>k<\/jats:italic>\n                    -mer statistics, enabling ANI-based taxa detection. On the Critical Assessment of Metagenome Interpretation II (CAMI2) Marine dataset, sylph was the most accurate profiling method of seven tested. For multisample profiling, sylph took &gt;10-fold less central processing unit time compared to Kraken2 and used 30-fold less memory. Sylph\u2019s ANI estimates provided an orthogonal signal to abundance, allowing for an ANI-based metagenome-wide association study for Parkinson disease (PD) against 289,232 genomes while confirming known butyrate\u2013PD associations at the strain level. Sylph took &lt;1\u2009min and 16\u2009GB of random-access memory to profile metagenomes against 85,205 prokaryotic and 2,917,516 viral genomes, detecting 30-fold more viral sequences in the human gut compared to RefSeq. Sylph offers precise, efficient profiling with accurate containment ANI estimation even for low-coverage genomes.\n                  <\/jats:p>","DOI":"10.1038\/s41587-024-02412-y","type":"journal-article","created":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T06:18:43Z","timestamp":1728368323000},"page":"1348-1359","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":119,"title":["Rapid species-level metagenome profiling and containment estimation with sylph"],"prefix":"10.1038","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6990-7829","authenticated-orcid":false,"given":"Jim","family":"Shaw","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8275-9576","authenticated-orcid":false,"given":"Yun William","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,8]]},"reference":[{"key":"2412_CR1","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1038\/nbt.3935","volume":"35","author":"C Quince","year":"2017","unstructured":"Quince, C., Walker, A. 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