Abstract
SummaryLongitudinal studies of human leucocyte telomere length often report a percentage of individuals whose telomeres appear to lengthen. However, based on theoretical considerations and empirical data, Steenstrup et al. (Nucleic Acids Research, 2013, vol 41(13): e131) concluded that this lengthening is unlikely to be a real biological phenomenon and is more likely to be an artefact of measurement error. We dispute the logic underlying this claim. We argue that Steenstrup et al.'s analysis is incomplete because it failed to compare predictions derived from assuming a scenario with no true telomere lengthening with alternative scenarios in which true lengthening occurs. To address this deficit, we built a computational model of telomere dynamics that allowed us to compare the predicted percentage of observed telomere length gainers given differing assumptions about measurement error and the true underling dynamics. We modelled a set of scenarios, all assuming measurement error, but both with and without true telomere lengthening. We found a range of scenarios assuming some true telomere lengthening that yielded either similar or better quantitative fits to the empirical data on the percentage of individuals showing apparent telomere lengthening. We conclude that although measurement error contributes to the prevalence of apparent telomere lengthening, Steenstrup et al.'s conclusion was too strong, and current data do not allow us to reject the hypothesis that true telomere lengthening is a real biological phenomenon in epidemiological studies. Our analyses highlight the need for process‐level models in the analysis of telomere dynamics.
Highlights
It follows that if measurement error is present, there is a nonzero probability that a proportion of individuals in a longitudinal study will be incorrectly classified at follow-up as telomere length (TL) gainers
Demonstrates the scenario in which there is no variation in the annual rate of attrition and all individuals’ telomeres shorten at the same, constant rate; the value of r has no effect if there is no variance in annual attrition, and all three panels in this column simulate the same dynamics
The bottom row demonstrates the effect of setting the autocorrelation between rate of attrition in successive years to one; this generates a constant rate of attrition within individuals, but variation in rate of attrition between individuals, with a small proportion of individuals consistently gaining TL when ra > 0
Summary
Cross-sectional and longitudinal studies of telomere dynamics show that, on average, leucocyte telomere length (TL) declines at a rate of 20–45 base pairs (bp) per year (Vaziri et al, 1993; Slagboom et al, 1994; Gardner et al, 2005; Aviv et al, 2009; Ehrlenbach et al, 2009; Farzaneh-Far et al, 2010; Chen et al, 2011; Kark et al, 2012; Steenstrup et al, 2013b; Bendix et al, 2014). Technical variation, measured as the intra- or interassay coefficient of variation (CV), has been estimated at 1.4–9.5% within laboratories (Martin-Ruiz et al, 2015) This CV translates into a standard deviation of 98–665 bp for a mean TL of 7000 bp, which is considerable in comparison with the annual attrition rates cited above. An important implication of measurement error is that repeated measures of the same sample are unlikely to be identical, and assuming that measurement error is unbiased and symmetrically distributed, on average 50% of second TL measurements on the same sample will be larger than the first It follows that if measurement error is present, there is a nonzero probability that a proportion of individuals in a longitudinal study will be incorrectly classified at follow-up as TL gainers. The conclusion is that observed telomere lengthening in longitudinal studies could be an artefact of measurement error (Steenstrup et al, 2013a,b; Verhulst et al, 2015)
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