Rediscussion on linearity between fibrosis stages and mortality risk in nonalcoholic fatty liver disease patients
Authors: Zhengtao Liu, Shuping Que, Adil Mardinoglu
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. The study was supported by grants from the Knut and Alice Wallenberg Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. To the Editor: We read with great interest the paper recently published in hepatology by Dulai et al.1 The authors performed a meta‐analysis to investigate the contribution of fibrosis progression to all‐cause/liver‐related mortality in nonalcoholic fatty liver disease patients based on previous cohort studies. However, the linearity between fibrosis and mortality was lacking a rigorous statistical test. It is worthy to reanalyze the continuous risk of fibrosis on a mortality indicator. In this paper, the authors suggested that liver‐related mortality increased with advanced fibrosis in an exponential manner. But this result was unreliable because it was achieved only through numerical change without consideration of 95% confidence intervals of risk and statistical significance on linearity examination. Therefore, we reexamined the linearity and nonlinearity for fibrosis severity on all‐cause/liver‐related mortality based on data provided in the paper by a previously described method.2 For all‐cause mortality, the results from generalized least‐squares regression in a fixed‐effect model revealed that the dose–response mortality risk ratio was 1.57 (95% confidence interval, 1.44‐1.70) in linear trend (P < 0.01), with insignificant intersubgroup heterogeneity (P = 0.70). No evidence supported a nonlinear relationship between fibrosis and all‐cause mortality based on a restricted cubic spline test within fixed‐effects models (P = 0.61; Fig. 1A). Unlike the exponential pattern emphasized in the paper, liver‐related mortality also increased with advanced fibrosis in nonalcoholic fatty liver disease patients with a linear trend (P < 0.01). Using the same methods as for all‐cause mortality, an approximately 160% increment in liver‐related mortality was seen advanced fibrosis stages (pooled mortality risk ratio, 2.60; 95% confidence interval, 1.87‐3.62, higher than mortality risk ratio on all‐cause mortality; P < 0.01) in combined studies with low heterogeneity (P = 0.97). Similarly, insignificance was observed in a nonlinearity test between fibrosis stage and liver‐related mortality (P = 0.90; Fig. 1B).Figure 1: Dose–response relations between fibrosis stage and risk ratio of (A) all‐cause and (B) liver‐related mortality. Data were fitted with fixed‐effects restricted cubic spline and generalized least squares models to estimate the covariances of mortality risk ratios. Solid line represents the fitted nonlinear trend between fibrosis stage and mortality risk ratio (P = 0.61 for A, P = 0.90 for B); lines with long dashes represent the corresponding 95% confidence intervals for the solid line; lines with short dashes represent the linear trend (P < 0.01 both for A and B).Hence, arbitrary estimation of the exposure–risk relationship based only on the seeming performance of the curve is unreasonable and might cause misleading interpretations. Our reanalysis confirmed the linearity and assessed relative risk extent for advanced fibrosis stage on all‐cause/liver‐related mortality, which is helpful to improve our knowledge of it.