{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T18:03:59Z","timestamp":1789581839299,"version":"build-2803163510"},"reference-count":59,"publisher":"National Academy of Sciences","issue":"38","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000025","name":"HHS | NIH | National Institute of Mental Health","doi-asserted-by":"publisher","award":["MH125235"],"award-info":[{"award-number":["MH125235"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"HHS | NIH | National Institute of Mental Health","doi-asserted-by":"publisher","award":["MH123184"],"award-info":[{"award-number":["MH123184"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014370","name":"Simons Foundation Autism Research Initiative","doi-asserted-by":"publisher","award":["SF1018804)"],"award-info":[{"award-number":["SF1018804)"]}],"id":[{"id":"10.13039\/100014370","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,9,22]]},"abstract":"<jats:p>\n                    A single gene can encode multiple versions of a protein, dubbed isoforms, with varying functionality. Cellular control of isoform abundances is critical for multiple aspects of biology and is only partially regulated by transcript levels. While long-read sequencing facilitates transcript quantification, quantifying the resulting protein isoforms on a large scale is a major challenge, complicating biological interpretation of transcript alterations. Standard \u201cbottom up\u201d mass spectrometry can assess only short portions of isoforms called peptides, and these peptides often map onto more than one isoform. We introduce\n                    <jats:inline-formula>\n                      <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" display=\"inline\" overflow=\"scroll\">\n                        <mml:mrow>\n                          <mml:mtext mathvariant=\"monospace\">PAQu<\/mml:mtext>\n                        <\/mml:mrow>\n                      <\/mml:math>\n                    <\/jats:inline-formula>\n                    (Protein isoform Abundance Quantification), a Bayesian method that leverages multiomic information from the peptidome and transcriptome to provide accurate estimates of isoform abundance even when peptide mapping is ambiguous.\n                    <jats:inline-formula>\n                      <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" display=\"inline\" overflow=\"scroll\">\n                        <mml:mrow>\n                          <mml:mtext mathvariant=\"monospace\">PAQu<\/mml:mtext>\n                        <\/mml:mrow>\n                      <\/mml:math>\n                    <\/jats:inline-formula>\n                    offers several advantages over existing methods in a unified framework. It provides uncertainty quantification, integrates multiomic information for improved accuracy, and provides a rigorous framework for hypothesis testing. Extensive simulations show that\n                    <jats:inline-formula>\n                      <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" display=\"inline\" overflow=\"scroll\">\n                        <mml:mrow>\n                          <mml:mtext mathvariant=\"monospace\">PAQu<\/mml:mtext>\n                        <\/mml:mrow>\n                      <\/mml:math>\n                    <\/jats:inline-formula>\n                    consistently outperforms competing methods in detecting differentially abundant protein isoforms and estimating their abundances. We use\n                    <jats:inline-formula>\n                      <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" display=\"inline\" overflow=\"scroll\">\n                        <mml:mrow>\n                          <mml:mtext mathvariant=\"monospace\">PAQu<\/mml:mtext>\n                        <\/mml:mrow>\n                      <\/mml:math>\n                    <\/jats:inline-formula>\n                    to investigate differences in isoform abundance levels between people with schizophrenia and control subjects, confirming a long-held hypothesis that levels of the C4A isoform of Complement Component 4 are increased in schizophrenia while C4B is not. These results demonstrate that\n                    <jats:inline-formula>\n                      <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" display=\"inline\" overflow=\"scroll\">\n                        <mml:mrow>\n                          <mml:mtext mathvariant=\"monospace\">PAQu<\/mml:mtext>\n                        <\/mml:mrow>\n                      <\/mml:math>\n                    <\/jats:inline-formula>\n                    can identify significant variations in isoform abundance levels not previously possible.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2614319123","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:37:27Z","timestamp":1789580247000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Estimating protein isoform abundances with PAQu"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2782-4846","authenticated-orcid":false,"given":"Lorenzo","family":"Testa","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05x2bcf33","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Statistics and Data Science, Carnegie Mellon University","place":["Pittsburgh"]},{"id":[{"id":"https:\/\/ror.org\/025602r80","id-type":"ROR","asserted-by":"publisher"}],"name":"L\u2019EMbeDS Department, Sant\u2019Anna School of Advanced Studies","place":["Pisa, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lambertus","family":"Klei","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Psychiatry, University of Pittsburgh School of Medicine","place":["Pittsburgh"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alesia","family":"Rengle","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Statistics, University of Pittsburgh","place":["Pittsburgh"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"K. Yocum","sequence":"additional","affiliation":[{"name":"A2IDEA, LLC.","place":["Ann Arbor"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3225-6778","authenticated-orcid":false,"given":"David A.","family":"Lewis","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Psychiatry, University of Pittsburgh School of Medicine","place":["Pittsburgh"]},{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Neuroscience, University of Pittsburgh","place":["Pittsburgh"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2524-4290","authenticated-orcid":false,"given":"Bernie","family":"Devlin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Psychiatry, University of Pittsburgh School of Medicine","place":["Pittsburgh"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8869-6254","authenticated-orcid":false,"given":"Kathryn","family":"Roeder","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05x2bcf33","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Statistics and Data Science, Carnegie Mellon University","place":["Pittsburgh"]},{"id":[{"id":"https:\/\/ror.org\/05x2bcf33","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Computational Biology, Carnegie Mellon University","place":["Pittsburgh"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew L.","family":"MacDonald","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Psychiatry, University of Pittsburgh School of Medicine","place":["Pittsburgh"]},{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Biomedical Mass Spectrometry Center, University of Pittsburgh","place":["Pittsburgh"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2012.07.083"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-060614-034316"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-022-00541-7"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-021-00486-7"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-021-00240-7"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat8127"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.adh0829"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-020-00737-2"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-024-01383-8"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/ahg.12437"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-01714-x"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-022-02624-y"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.R500012-MCP200"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.O110.007088"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-1178-4_19"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1021\/pr070230d"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.3390\/proteomes9010015"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4256"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.8b00310"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btaf450"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1214\/009053604000001147"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-0-387-92407-6"},{"key":"e_1_3_4_23_2","first-page":"275","article-title":"False discovery rates: A new deal","volume":"18","author":"Stephens M.","year":"2017","unstructured":"M. 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