A review and critique of the statistical methods used to generate reference values in pediatric echocardiography

Several articles have proposed echocardiographic reference values in normal pediatric subjects, but adequate validation is often lacking and has not been reviewed. The aim of this study was to review published reference values in pediatric two-dimensional and M-mode echocardiography with a specific focus on the adequacy of the statistical and mathematical methods used to normalize echocardiographic measurements. All articles proposing reference values for transthoracic pediatric echocardiography were reviewed. The types of measurements, the methods of normalization, the regression models used, and the methods used to detect potential bias in proposed reference values were abstracted. The detection of residual associations, residual heteroscedasticity, and departures from the normal distribution theory predictions were specifically analyzed. Fifty-two studies met the inclusion criteria. Most authors (87%) used parametric normalization to account for body size, but their approaches were very heterogeneous. Linear regression and indexing were the most common models. Heteroscedasticity was often present but was mentioned in only 27% of studies. The absence of residual heteroscedasticity and residual associations between the normalized measurements and the independent variables were mentioned in only 9% and 22% of the studies, respectively. Only 14% of studies documented that the distribution of the residual values was appropriate for Z score calculation or that the proportion of subjects falling outside the reference range was appropriate. Statistical suitability of the proposed reference ranges was often incompletely documented. This review underlines the great need for better standardization in echocardiographic measurement normalization.