How effectively can HIV phylogenies be used to measure heritability?
OBJECTIVE
The severity of HIV-1 infection, measured by set-point viral load (SPVL), is highly variable between individuals. Its heritability between infections quantifies the control the pathogen genotype has over disease severity. Heritability estimates vary widely between studies, but differences in methods make comparison difficult. Phylogenetic comparative analysis offers measures of phylogenetic signal, but it is unclear how to interpret them in terms of the fraction of variance in SPVL controlled by the virus genotype.


METHODS
We present computational methods which link statistics summarizing phylogenetic signal to heritability, h(2) in order to test for and quantify it. We re-analyse data from Switzerland and Uganda, and apply it to new data from the Netherlands. We systematically compare established and new (e.g. phylogenetic pairs, PP) phylogenetic signal statistics.


RESULTS
Heritability estimates varied by method and dataset. Several methods were consistently able to detect simulated heritability above , but none below. Pagel's λ was the most robust and sensitive. The PP method found no heritability in the Netherlands data, whereas Pagel's λ found significant heritability only in a narrow subdivision (P = 0.038). Heritability was estimated at h(2) = 0.52 (95% confidence interval 0.00-0.63).


CONCLUSIONS
This standardized measure, h(2), allows comparability of heritability between cohorts. We confirm high heritability in Swiss data, but neither in Ugandan data nor in the Netherlands, where it is barely significant or undetectable. Existing phylogenetic methods are ill-suited for detecting heritability below , which may nonetheless be biologically important.
Medical Research Council Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College, London, UK; Institute for Integrative Biology, ETH Zürich, Zürich, Switzerland; Lab MIVEGEC UMR CNRS 5290, IRD 224, UM1, UM2, Montpellier, France; Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zürich, University of Zürich, Zürich, Switzerland; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Baltimore, MD, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; and Stichting HIV Monitoring, Amsterdam, The Netherlands.
George
G
Shirreff
Samuel
S
Alizon
Anne
A
Cori
Huldrych F
HF
Günthard
Oliver
O
Laeyendecker
Ard
A
van Sighem
Daniela
D
Bezemer
Christophe
C
Fraser
HIV-1; heritability; phylogenetic comparative analysis; phylogenetic signal; set-point viral load; virulence