title: Survival analysis on aggregate data to assess time to sero-conversion after experimental infection with Bovine Leukemia virus.
abstract: Bovine Leukemia virus (BLV) is a ubiquitous retrovirus that affects mainly cattle. Knowledge of the precise moment of infection is fundamental for identification and evaluation of factors related to BLV transmission. Systematic reviews and meta-analyses provide good evidence on the effects of medical interventions. The objectives were to estimate time to sero-conversion after experimental infection using data from retrieved literature and to detect factors that may influence the length of that interval using survival analysis on pooled data. An analysis using aggregate data from 36 studies totalling 438 observations was performed. From this, four sets were created and analysed by interval-censored accelerated failure time models (AFT) with different distributions (exponential, Weibull, log-logistic, lognormal and generalized gamma), and some variants of the Cox model (Andersen-Gill, smoothing splines) with and without a frailty effect. The AFT gamma model fit best and the estimated median time to sero-conversion in the null model was 57 days (95% confidence interval (CI): 49; 75) using all data and 47 days (95% CI: 39; 55) when only studies using experimental inoculation were considered. Some factors were consistently associated with time to sero-conversion. These included exposure by animal-to-animal contact (resulting in a seven-fold increase in time to sero-conversion compared to direct inoculation), diagnostic method to detect sero-conversion (time to sero-conversion was 1.4 times shorter when AGID was used compared to ELISA), and transmission by insect bites (biological media) delayed sero-conversion 2.3 times compared transmission via needles or other inanimate media. After fitting a frailty Cox model, results showed that sero-conversion in susceptible animals after infection using donors, in which presence of virus before the experiment started was confirmed, increased the hazard of sero-conversion two times in comparison with donors in which virus presence was not confirmed before start of the experiment. Inoculation with blood decreased the hazard 2.5 times in comparison with lymphocyte suspensions. Heterogeneity due to different research groups was also present. Finally, a Cox model with smoothing splines contained three variables: research group, route of inoculation and a non-linear spline for infective dose. In conclusion, it can be stated some factors that influence the time to sero-conversion were identified and quantified and that a moderate influence of research centre existed. These results may contribute to the estimation of the most probable times of infection in field conditions and in a better evaluation of control measures.
authors.affiliation: Quantitative Veterinary Epidemiology Group, Wageningen Institute of Animal Sciences Wageningen, P.O. Box 338, 6700 AH Wageningen, The Netherlands. gustavo.monti@wur.nl
authors.forename: G E
authors.initials: GE
authors.lastname: Monti
authors.forename: K
authors.initials: K
authors.lastname: Frankena
mesh_terms: D000818:Animals; D002417:Cattle; D016583:Enzootic Bovine Leukosis / Q000276:immunology* / Q000821:virology; D005260:Female; D001909:Leukemia Virus, Bovine / Q000276:immunology*; D015233:Models, Statistical; D015999:Multivariate Analysis; D016019:Survival Analysis; D013997:Time Factors