{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T04:38:45Z","timestamp":1777437525129,"version":"3.51.4"},"reference-count":69,"publisher":"Oxford University Press (OUP)","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Given the inherent dynamics of a viral quasispecies, we are often interested in the comparison of diversity indices of sequential samples of a patient, or in the comparison of diversity indices of virus in groups of patients in a treated versus control design. It is then important to make sure that the diversity measures from each sample may be compared with no bias and within a consistent statistical framework. In the present report, we review some indices often used as measures for viral quasispecies complexity and provide means for statistical inference, applying procedures taken from the ecology field. In particular, we examine the Shannon entropy and the mutation frequency, and we discuss the appropriateness of different normalization methods of the Shannon entropy found in the literature. By taking amplicons ultra-deep pyrosequencing (UDPS) raw data as a surrogate of a real hepatitis C virus viral population, we study through in-silico sampling the statistical properties of these indices under two methods of viral quasispecies sampling, classical cloning followed by Sanger sequencing (CCSS) and next-generation sequencing (NGS) such as UDPS. We propose solutions specific to each of the two sampling methods\u2014CCSS and NGS\u2014to guarantee statistically conforming conclusions as free of bias as possible.<\/jats:p>\n               <jats:p>Contact: \u00a0josep.gregori@gmail.com<\/jats:p>\n               <jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online<\/jats:p>","DOI":"10.1093\/bioinformatics\/btt768","type":"journal-article","created":{"date-parts":[[2014,1,4]],"date-time":"2014-01-04T02:03:14Z","timestamp":1388800994000},"page":"1104-1111","source":"Crossref","is-referenced-by-count":62,"title":["Inference with viral quasispecies diversity indices: clonal and NGS approaches"],"prefix":"10.1093","volume":"30","author":[{"given":"Josep","family":"Gregori","sequence":"first","affiliation":[{"name":"1 Liver Unit, Internal Medicine Lab Malalties Hep\u00e0tiques, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035 Barcelona, Spain, 2Roche Diagnostics SL, 08174, Sant Cugat del Vall\u00e8s, Spain, 3Statistics Department, Biology Faculty, Barcelona University, 08028, Barcelona, Spain, 4CIBER de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, 28029 Madrid, Spain, 5Centro de Biolog\u00eda Molecular Severo Ochoa (CSIC-UAM), Campus de Cantoblanco, 28049, Madrid, Spain, 6Bioinformatics and Statistics Unit, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035, Barcelona, Spain, 7Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Barcelona, Spain and 8Biochemistry Unit. Virology Unit\/Microbiology Department, HUVH, 08035 Barcelona, Spain"},{"name":"1 Liver Unit, Internal Medicine Lab Malalties Hep\u00e0tiques, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035 Barcelona, Spain, 2Roche Diagnostics SL, 08174, Sant Cugat del Vall\u00e8s, Spain, 3Statistics Department, Biology Faculty, Barcelona University, 08028, Barcelona, Spain, 4CIBER de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, 28029 Madrid, Spain, 5Centro de Biolog\u00eda Molecular Severo Ochoa (CSIC-UAM), Campus de Cantoblanco, 28049, Madrid, Spain, 6Bioinformatics and Statistics Unit, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035, Barcelona, Spain, 7Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Barcelona, Spain and 8Biochemistry Unit. Virology Unit\/Microbiology Department, HUVH, 08035 Barcelona, Spain"},{"name":"1 Liver Unit, Internal Medicine Lab Malalties Hep\u00e0tiques, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035 Barcelona, Spain, 2Roche Diagnostics SL, 08174, Sant Cugat del Vall\u00e8s, Spain, 3Statistics Department, Biology Faculty, Barcelona University, 08028, Barcelona, Spain, 4CIBER de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, 28029 Madrid, Spain, 5Centro de Biolog\u00eda Molecular Severo Ochoa (CSIC-UAM), Campus de Cantoblanco, 28049, Madrid, Spain, 6Bioinformatics and Statistics Unit, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035, Barcelona, Spain, 7Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Barcelona, Spain and 8Biochemistry Unit. Virology Unit\/Microbiology Department, HUVH, 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miquel","family":"Salicr\u00fa","sequence":"additional","affiliation":[{"name":"1 Liver Unit, Internal Medicine Lab Malalties Hep\u00e0tiques, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035 Barcelona, Spain, 2Roche Diagnostics SL, 08174, Sant Cugat del Vall\u00e8s, Spain, 3Statistics Department, Biology Faculty, Barcelona University, 08028, Barcelona, Spain, 4CIBER de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, 28029 Madrid, Spain, 5Centro de Biolog\u00eda Molecular Severo Ochoa (CSIC-UAM), Campus de Cantoblanco, 28049, Madrid, Spain, 6Bioinformatics and Statistics Unit, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035, Barcelona, Spain, 7Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Barcelona, Spain and 8Biochemistry Unit. Virology Unit\/Microbiology Department, HUVH, 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esteban","family":"Domingo","sequence":"additional","affiliation":[{"name":"1 Liver Unit, Internal Medicine Lab Malalties Hep\u00e0tiques, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035 Barcelona, Spain, 2Roche Diagnostics SL, 08174, Sant Cugat del Vall\u00e8s, Spain, 3Statistics Department, Biology Faculty, Barcelona University, 08028, Barcelona, Spain, 4CIBER de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, 28029 Madrid, Spain, 5Centro de Biolog\u00eda Molecular Severo Ochoa (CSIC-UAM), Campus de Cantoblanco, 28049, Madrid, Spain, 6Bioinformatics and Statistics Unit, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035, Barcelona, Spain, 7Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Barcelona, Spain and 8Biochemistry Unit. Virology Unit\/Microbiology Department, HUVH, 08035 Barcelona, Spain"},{"name":"1 Liver Unit, Internal Medicine Lab Malalties Hep\u00e0tiques, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035 Barcelona, Spain, 2Roche Diagnostics SL, 08174, Sant Cugat del Vall\u00e8s, Spain, 3Statistics Department, Biology Faculty, Barcelona University, 08028, Barcelona, Spain, 4CIBER de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, 28029 Madrid, Spain, 5Centro de Biolog\u00eda Molecular Severo Ochoa (CSIC-UAM), Campus de Cantoblanco, 28049, Madrid, Spain, 6Bioinformatics and Statistics Unit, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035, Barcelona, Spain, 7Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Barcelona, Spain and 8Biochemistry Unit. Virology Unit\/Microbiology Department, HUVH, 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex","family":"Sanchez","sequence":"additional","affiliation":[{"name":"1 Liver Unit, Internal Medicine Lab Malalties Hep\u00e0tiques, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035 Barcelona, Spain, 2Roche Diagnostics SL, 08174, Sant Cugat del Vall\u00e8s, Spain, 3Statistics Department, Biology Faculty, Barcelona University, 08028, Barcelona, Spain, 4CIBER de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, 28029 Madrid, Spain, 5Centro de Biolog\u00eda Molecular Severo Ochoa (CSIC-UAM), Campus de Cantoblanco, 28049, Madrid, Spain, 6Bioinformatics and Statistics Unit, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035, Barcelona, Spain, 7Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Barcelona, Spain and 8Biochemistry Unit. Virology Unit\/Microbiology Department, HUVH, 08035 Barcelona, Spain"},{"name":"1 Liver Unit, Internal Medicine Lab Malalties Hep\u00e0tiques, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035 Barcelona, Spain, 2Roche Diagnostics SL, 08174, Sant Cugat del Vall\u00e8s, Spain, 3Statistics Department, Biology Faculty, Barcelona University, 08028, Barcelona, Spain, 4CIBER de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, 28029 Madrid, Spain, 5Centro de Biolog\u00eda Molecular Severo Ochoa (CSIC-UAM), Campus de Cantoblanco, 28049, Madrid, Spain, 6Bioinformatics and Statistics Unit, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035, Barcelona, Spain, 7Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Barcelona, Spain and 8Biochemistry Unit. Virology Unit\/Microbiology Department, HUVH, 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan I.","family":"Esteban","sequence":"additional","affiliation":[{"name":"1 Liver Unit, Internal Medicine Lab Malalties Hep\u00e0tiques, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035 Barcelona, Spain, 2Roche Diagnostics SL, 08174, Sant Cugat del Vall\u00e8s, Spain, 3Statistics Department, Biology Faculty, Barcelona University, 08028, Barcelona, Spain, 4CIBER de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, 28029 Madrid, Spain, 5Centro de Biolog\u00eda Molecular Severo Ochoa (CSIC-UAM), Campus de Cantoblanco, 28049, Madrid, Spain, 6Bioinformatics and Statistics Unit, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035, Barcelona, Spain, 7Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Barcelona, Spain and 8Biochemistry Unit. Virology Unit\/Microbiology Department, HUVH, 08035 Barcelona, Spain"},{"name":"1 Liver Unit, Internal Medicine Lab Malalties Hep\u00e0tiques, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035 Barcelona, Spain, 2Roche Diagnostics SL, 08174, Sant Cugat del Vall\u00e8s, Spain, 3Statistics Department, Biology Faculty, Barcelona University, 08028, Barcelona, Spain, 4CIBER de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, 28029 Madrid, Spain, 5Centro de Biolog\u00eda Molecular Severo Ochoa (CSIC-UAM), Campus de Cantoblanco, 28049, Madrid, Spain, 6Bioinformatics and Statistics Unit, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035, Barcelona, Spain, 7Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Barcelona, Spain and 8Biochemistry Unit. Virology Unit\/Microbiology Department, HUVH, 08035 Barcelona, Spain"},{"name":"1 Liver Unit, Internal Medicine Lab Malalties Hep\u00e0tiques, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035 Barcelona, Spain, 2Roche Diagnostics SL, 08174, Sant Cugat del Vall\u00e8s, Spain, 3Statistics Department, Biology Faculty, Barcelona University, 08028, Barcelona, Spain, 4CIBER de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, 28029 Madrid, Spain, 5Centro de Biolog\u00eda Molecular Severo Ochoa (CSIC-UAM), Campus de Cantoblanco, 28049, Madrid, Spain, 6Bioinformatics and Statistics Unit, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035, Barcelona, Spain, 7Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Barcelona, Spain and 8Biochemistry Unit. Virology Unit\/Microbiology Department, HUVH, 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisco","family":"Rodr\u00edguez-Fr\u00edas","sequence":"additional","affiliation":[{"name":"1 Liver Unit, Internal Medicine Lab Malalties Hep\u00e0tiques, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035 Barcelona, Spain, 2Roche Diagnostics SL, 08174, Sant Cugat del Vall\u00e8s, Spain, 3Statistics Department, Biology Faculty, Barcelona University, 08028, Barcelona, Spain, 4CIBER de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, 28029 Madrid, Spain, 5Centro de Biolog\u00eda Molecular Severo Ochoa (CSIC-UAM), Campus de Cantoblanco, 28049, Madrid, Spain, 6Bioinformatics and Statistics Unit, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035, Barcelona, Spain, 7Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Barcelona, Spain and 8Biochemistry Unit. Virology Unit\/Microbiology Department, HUVH, 08035 Barcelona, Spain"},{"name":"1 Liver Unit, Internal Medicine Lab Malalties Hep\u00e0tiques, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035 Barcelona, Spain, 2Roche Diagnostics SL, 08174, Sant Cugat del Vall\u00e8s, Spain, 3Statistics Department, Biology Faculty, Barcelona University, 08028, Barcelona, Spain, 4CIBER de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, 28029 Madrid, Spain, 5Centro de Biolog\u00eda Molecular Severo Ochoa (CSIC-UAM), Campus de Cantoblanco, 28049, Madrid, Spain, 6Bioinformatics and Statistics Unit, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035, Barcelona, Spain, 7Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Barcelona, Spain and 8Biochemistry Unit. Virology Unit\/Microbiology Department, HUVH, 08035 Barcelona, Spain"},{"name":"1 Liver Unit, Internal Medicine Lab Malalties Hep\u00e0tiques, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035 Barcelona, Spain, 2Roche Diagnostics SL, 08174, Sant Cugat del Vall\u00e8s, Spain, 3Statistics Department, Biology Faculty, Barcelona University, 08028, Barcelona, Spain, 4CIBER de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, 28029 Madrid, Spain, 5Centro de Biolog\u00eda Molecular Severo Ochoa (CSIC-UAM), Campus de Cantoblanco, 28049, Madrid, Spain, 6Bioinformatics and Statistics Unit, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035, Barcelona, Spain, 7Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Barcelona, Spain and 8Biochemistry Unit. Virology Unit\/Microbiology Department, HUVH, 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josep","family":"Quer","sequence":"additional","affiliation":[{"name":"1 Liver Unit, Internal Medicine Lab Malalties Hep\u00e0tiques, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035 Barcelona, Spain, 2Roche Diagnostics SL, 08174, Sant Cugat del Vall\u00e8s, Spain, 3Statistics Department, Biology Faculty, Barcelona University, 08028, Barcelona, Spain, 4CIBER de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, 28029 Madrid, Spain, 5Centro de Biolog\u00eda Molecular Severo Ochoa (CSIC-UAM), Campus de Cantoblanco, 28049, Madrid, Spain, 6Bioinformatics and Statistics Unit, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035, Barcelona, Spain, 7Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Barcelona, Spain and 8Biochemistry Unit. Virology Unit\/Microbiology Department, HUVH, 08035 Barcelona, Spain"},{"name":"1 Liver Unit, Internal Medicine Lab Malalties Hep\u00e0tiques, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035 Barcelona, Spain, 2Roche Diagnostics SL, 08174, Sant Cugat del Vall\u00e8s, Spain, 3Statistics Department, Biology Faculty, Barcelona University, 08028, Barcelona, Spain, 4CIBER de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, 28029 Madrid, Spain, 5Centro de Biolog\u00eda Molecular Severo Ochoa (CSIC-UAM), Campus de Cantoblanco, 28049, Madrid, Spain, 6Bioinformatics and Statistics Unit, Vall d\u2019Hebron Institut Recerca (VHIR-HUVH), 08035, Barcelona, Spain, 7Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Barcelona, Spain and 8Biochemistry Unit. 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