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replication. Assessing quasispecies structure and diversity is crucial for understanding viral evolution, adaptation, and response to antiviral treatments. However, comparing single quasispecies observations from individual biosamples, especially at different infection or treatment time points, presents statistical challenges. Traditional inferential tests are inapplicable due to the lack of replicate observations, and resampling-based approaches such as the bootstrap and jackknife are limited by biases and non-independence, particularly for diversity indices sensitive to rare haplotypes. In this study, we address these limitations by applying the delta method to derive analytical variances for a set of quasispecies structure indicators specifically designed to assess the quasispecies maturation state. We demonstrate the utility of this approach using high-depth next-generation sequencing data from hepatitis C virus (HCV) quasispecies evolving in vitro under various conditions, including free evolution and exposure to antiviral or mutagenic treatments. Our results reveal that with highly fit HCV quasispecies, sofosbuvir inhibits quasispecies genetic diversity, while mutagenic treatments accelerate maturation, compared to untreated controls. We emphasize the interpretation of results through absolute differences, log-fold changes, and standardized effect sizes, moving beyond mere statistical significance. This framework enables robust, quantitative comparisons of quasispecies diversity from single observations, providing valuable insights into viral adaptation and treatment response. The R code and session info with required libraries and versions is provided in the supplementary material.<\/jats:p>","DOI":"10.3390\/microorganisms13092029","type":"journal-article","created":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T13:27:44Z","timestamp":1756733264000},"page":"2029","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Viral Quasispecies Inference from Single Observations\u2014Mutagens as Accelerators of Quasispecies Evolution"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4253-8015","authenticated-orcid":false,"given":"Josep","family":"Gregori","sequence":"first","affiliation":[{"name":"Liver Diseases-Viral Hepatitis, Liver Unit, Vall d\u2019Hebron Institute of Research (VHIR), Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9644-5626","authenticated-orcid":false,"given":"Miquel","family":"Salicr\u00fa","sequence":"additional","affiliation":[{"name":"Statistics Department, Biology Faculty, University of Barcelona, 08028 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3428-2168","authenticated-orcid":false,"given":"Marta","family":"Ib\u00e1\u00f1ez-Lligo\u00f1a","sequence":"additional","affiliation":[{"name":"Liver Diseases-Viral Hepatitis, Liver Unit, Vall d\u2019Hebron Institute of Research (VHIR), Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain"},{"name":"Medicine Department, Universitat Autonoma de Barcelona (UAB), Campus de la UAB, Pla\u00e7a C\u00edvica, 08193 Bellaterra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0307-7455","authenticated-orcid":false,"given":"Sergi","family":"Colomer-Castell","sequence":"additional","affiliation":[{"name":"Liver Diseases-Viral Hepatitis, Liver Unit, Vall d\u2019Hebron Institute of Research (VHIR), Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain"},{"name":"Biochemistry and Molecular Biology Department, Universitat Autonoma de Barcelona (UAB), Campus de la UAB, Pla\u00e7a C\u00edvica, 08193 Bellaterra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0132-7027","authenticated-orcid":false,"given":"Carolina","family":"Campos","sequence":"additional","affiliation":[{"name":"Liver Diseases-Viral Hepatitis, Liver Unit, Vall d\u2019Hebron Institute of Research (VHIR), Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain"},{"name":"Biochemistry and Molecular Biology Department, Universitat Autonoma de Barcelona (UAB), Campus de la UAB, Pla\u00e7a C\u00edvica, 08193 Bellaterra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2058-0370","authenticated-orcid":false,"given":"Alvaro","family":"Gonz\u00e1lez-Camuesco","sequence":"additional","affiliation":[{"name":"Liver Diseases-Viral Hepatitis, Liver Unit, Vall d\u2019Hebron Institute of Research (VHIR), Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0014-084X","authenticated-orcid":false,"given":"Josep","family":"Quer","sequence":"additional","affiliation":[{"name":"Liver Diseases-Viral Hepatitis, Liver Unit, Vall d\u2019Hebron Institute of Research (VHIR), Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain"},{"name":"Medicine Department, Universitat Autonoma de Barcelona (UAB), Campus de la UAB, Pla\u00e7a C\u00edvica, 08193 Bellaterra, Spain"},{"name":"Biochemistry and Molecular Biology Department, Universitat Autonoma de Barcelona (UAB), Campus de la UAB, Pla\u00e7a C\u00edvica, 08193 Bellaterra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e1008271","DOI":"10.1371\/journal.pgen.1008271","article-title":"Viral quasispecies","volume":"15","author":"Domingo","year":"2019","journal-title":"PLoS Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1128\/MMBR.05023-11","article-title":"Viral Quasispecies Evolution","volume":"76","author":"Domingo","year":"2012","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1146\/annurev-virology-091919-105900","article-title":"Historical Perspective on the Discovery of the Quasispecies Concept","volume":"8","author":"Domingo","year":"2021","journal-title":"Annu. Rev. Virol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Todt, D., Walter, W., Brown, R., and Steinmann, E. (2016). Mutagenic Effects of Ribavirin on Hepatitis E Virus\u2014Viral Extinction versus Selection of Fitness-Enhancing Mutations. Viruses, 8.","DOI":"10.3390\/v8100283"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Gregori, J., Colomer-Castell, S., Campos, C., Iba\u00f1ez-Lligo\u00f1a, M., Garcia-Cehic, D., Rando-Segura, A., Adombie, C., Pint\u00f3, R., Guix, S., and Bosch, A. (2022). Quasispecies Fitness Partition to Characterize the Molecular Status of a Viral Population. Negative Effect of Early Ribavirin Discontinuation in a Chronically Infected HEV Patient. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232314654"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Colomer-Castell, S., Gregori, J., Garcia-Cehic, D., Riveiro-Barciela, M., Buti, M., Rando-Segura, A., Vico-Romero, J., Campos, C., Iba\u00f1ez-Lligo\u00f1a, M., and Adombi, C.M. (2023). In-Host HEV Quasispecies Evolution Shows the Limits of Mutagenic Antiviral Treatments. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242417185"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Gregori, J., Iba\u00f1ez-Lligo\u00f1a, M., Colomer-Castell, S., Garcia-Cehic, D., Campos, C., and Quer, J. (2024). Association of liver damage and quasispecies maturity in chronic HCV patients: The fate of a quasispecies. Microorganisms, 12.","DOI":"10.3390\/microorganisms12112213"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.1080\/03610929308831131","article-title":"Asymptotic distributions of (h,Fi)-entropies","volume":"22","author":"Salicru","year":"1993","journal-title":"Commun. Stat. Theory Methods"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1080\/03610929708831929","article-title":"Large sample behavior of entropy measures when parameters are estimated","volume":"26","author":"Pardo","year":"1997","journal-title":"Commun. Stat.-Theory Methods"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Rey, A., Frery, A., Lucini, M., Gambini, J., Chagas, E., and Ramos, H. (2023). Asymptotic Distribution of Certain Types of Entropy under the Multinomial Law. Entropy, 25.","DOI":"10.3390\/e25050734"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Efron, B., and Tibshirani, R. (1994). An Introduction to the Bootstrap, Chapman and Hall\/CRC. [1st ed.].","DOI":"10.1201\/9780429246593"},{"key":"ref_12","unstructured":"McCabe, W. (2005). Bootstrap Methods and Permutation Tests. Introduction to the Practice of Statistics, Freeman and Co.. [5th ed.]. Chapter 14."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ramachandran, K., and Tsokos, C. (2021). Chapter 13\u2014Empirical methods. Mathematical Statistics with Applications in R (Third Edition), Academic Press. [3rd ed.].","DOI":"10.1016\/B978-0-12-817815-7.00013-0"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Gregori, J., Iba\u00f1ez-Lligo\u00f1a, M., Colomer-Castell, S., Campos, C., and Quer, J. (2024). Virus Quasispecies Rarefaction: Subsampling with or without Replacement?. Viruses, 16.","DOI":"10.3390\/v16050710"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1214\/aos\/1176347263","article-title":"A general theory for jackknife variance estimation","volume":"17","author":"Shao","year":"1989","journal-title":"Ann. Stat."},{"key":"ref_16","unstructured":"Shao, J. (1988). Consistency of Jackknife Variance Estimators. Technical Report 88-58, Purdue University, Department of Statistics."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1080\/02331889108802282","article-title":"Consistency of jackknife variance estimators jun","volume":"22","author":"Shao","year":"1991","journal-title":"Statistics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1007\/s13571-023-00305-9","article-title":"A History of the Delta Method and Some New Results","volume":"85","author":"Bera","year":"2023","journal-title":"Sankhya B"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Hosmer, D., Lemeshow, S., and May, S. (2008). Appendix 1: The Delta Method. Applied Survival Analysis: Regression Modeling of Time-to-Event Data, John Wiley and Sons, Inc.","DOI":"10.1002\/9780470258019"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1080\/00031305.2012.687494","article-title":"Who invented the Delta Method?","volume":"66","author":"VerHoef","year":"2012","journal-title":"Am. Stat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3786","DOI":"10.1128\/AAC.00581-16","article-title":"Barrier-Independent, Fitness-Associated Differences in Sofosbuvir Efficacy against Hepatitis C Virus","volume":"60","author":"Gallego","year":"2016","journal-title":"Antimicrob Agents Chemother"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.virol.2018.07.030","article-title":"Resistance of high fitness hepatitis C virus to lethal mutagenesis","volume":"523","author":"Gallego","year":"2018","journal-title":"Virology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e02505-16","DOI":"10.1128\/JVI.02505-16","article-title":"Internal Disequilibria and Phenotypic Diversification during Replication of Hepatitis C Virus in a Noncoevolving Cellular Environment","volume":"91","author":"Moreno","year":"2017","journal-title":"J. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Crespo, C., Gallego, I., Soria, M., de \u00c1vila, A., Mart\u00ednez-Gonz\u00e1lez, B., V\u00e1zquez-Sirvent, L., Lobo-Vega, R., Moreno, E., G\u00f3mez, J., and Briones, C. (2021). Population Disequilibrium as Promoter of Adaptive Explorations in Hepatitis C Virus. Viruses, 13.","DOI":"10.3390\/v13040616"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Gregori, J., Colomer-Castell, S., Iba\u00f1ez-Lligo\u00f1a, M., Garcia-Cehic, D., Campos, C., Buti, M., Riveiro-Barciela, M., Andr\u00e9s, C., Pi\u00f1ana, M., and Gonz\u00e1lez-S\u00e1nchez, A. (2024). In-Host Flat-like Quasispecies: Characterization Methods and Clinical Implications. Microorganisms, 12.","DOI":"10.3390\/microorganisms12051011"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s40488-018-0083-x","article-title":"Mean and variance of ratios of proportions from categories of a multinomial distribution","volume":"5","author":"Duris","year":"2018","journal-title":"J. Stat. Distrib. Appl."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"328","DOI":"10.5395\/rde.2015.40.4.328","article-title":"Statistical notes for clinical researchers: Effect size","volume":"40","author":"Kim","year":"2015","journal-title":"Restor Dent. Endod."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1111\/j.1469-185X.2007.00027.x","article-title":"Effect size, confidence interval and statistical significance: A practical guide for biologists","volume":"82","author":"Nakagawa","year":"2007","journal-title":"Biol. Rev. Camb. Philos. Soc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1037\/a0028086","article-title":"On effect size","volume":"17","author":"Kelley","year":"2012","journal-title":"Psychol. Methods"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"26","DOI":"10.22237\/jmasm\/1257035100","article-title":"New Effect Size Rules of Thumb","volume":"8","author":"Sawilowsky","year":"2009","journal-title":"J. Mod. Appl. Stat. Methods"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1002\/hep.22550","article-title":"Cell culture-produced hepatitis C virus does not infect peripheral blood mononuclear cells","volume":"48","author":"Marukian","year":"2008","journal-title":"Hepatology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7593","DOI":"10.1128\/JVI.02824-12","article-title":"Response of Hepatitis C Virus to Long-Term Passage in the Presence of Alpha Interferon: Multiple Mutations and a Common Phenotype","volume":"87","author":"Perales","year":"2013","journal-title":"J. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"12098","DOI":"10.1128\/JVI.01860-14","article-title":"Increased replicative fitness can lead to decreased drug sensitivity of hepatitis C virus","volume":"88","author":"Sheldon","year":"2014","journal-title":"J. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e0164691","DOI":"10.1371\/journal.pone.0164691","article-title":"Lethal Mutagenesis of Hepatitis C Virus Induced by Favipiravir","volume":"11","author":"Gallego","year":"2016","journal-title":"PLoS ONE"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e71039","DOI":"10.1371\/journal.pone.0071039","article-title":"Extinction of Hepatitis C Virus by Ribavirin in Hepatoma Cells Involves Lethal Mutagenesis","volume":"8","author":"Sheldon","year":"2013","journal-title":"PLoS ONE"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e0204877","DOI":"10.1371\/journal.pone.0204877","article-title":"Rare haplotype load as marker for lethal mutagenesis","volume":"13","author":"Gregori","year":"2018","journal-title":"PLoS ONE"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.tibs.2023.01.009","article-title":"Trials and tribulations of statistical significance in biochemistry and omics","volume":"48","author":"Montero","year":"2023","journal-title":"Trends Biochem. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3954","DOI":"10.1021\/acs.jproteome.7b00418","article-title":"Experimental Design in Clinical \u2019Omics Biomarker Discovery","volume":"16","author":"Forshed","year":"2017","journal-title":"J. Proteome. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1038\/s43587-023-00448-4","article-title":"Considerations for reproducible omics in aging research","volume":"3","author":"Singh","year":"2023","journal-title":"Nat. Aging"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1006\/viro.2000.0320","article-title":"Viruses at the edge of adaptation","volume":"270","author":"Domingo","year":"2000","journal-title":"Virology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.4155\/fmc-2018-0457","article-title":"The increasing impact of lethal mutagenesis of viruses","volume":"11","author":"Perales","year":"2019","journal-title":"Future Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Hassine, I., M\u2019hadheb, M., and Men\u00e9ndez-Arias, L. (2022). Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity. Viruses, 14.","DOI":"10.3390\/v14040841"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2957","DOI":"10.1093\/bioinformatics\/btr507","article-title":"FLASH: Fast length adjustment of short reads to improve genome assemblies","volume":"27","author":"Magoc","year":"2011","journal-title":"Bioinformatics"}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/13\/9\/2029\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:36:00Z","timestamp":1760034960000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/13\/9\/2029"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,30]]},"references-count":43,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["microorganisms13092029"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms13092029","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,30]]}}}