State-of-the-Art Review Article
A Review and Critique of the Statistical Methods Used to Generate Reference Values in Pediatric Echocardiography

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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.

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Literature Search Strategy

A search of the National Library of Medicine's PubMed database was performed using the Medical Subject Headings controlled vocabulary from the National Library of Medicine. The search strategy was built to retrieve all articles containing the Medical Subject Headings terms “echocardiography” and “reference values” or their equivalents: (reference values OR biometry OR anthropometry OR regression analysis) AND {echocardiography OR [ultrasonography AND (heart OR cardiovascular system)]}. We

Search Results and Selected Articles

The search strategy returned 1,016 articles. Initial screening by title and abstract identified 117 potentially relevant articles. Sixty-five were further excluded (27 did not propose reference values, five were related to other echocardiographic modalities, 20 did not include pediatric data, five did not include normal subjects, and eight were conducted before 1980), leaving 52 articles for analysis.7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31

Discussion

In pediatric and congenital cardiology, many clinical, interventional, and surgical decisions are based on the sizes of cardiac structures. Moreover, follow-up of children with repaired and unrepaired cardiac defects often depends on the identification of structural growth that deviates from expected. The development of reliable and validated reference values in transthoracic echocardiography is thus of great importance, because a biased or inaccurate cardiac growth curve could lead to

Conclusions

Choice of population, technical standardization of echocardiographic measurements, and detailed strategies for model selection were outside the scope of this review, as they were recently addressed elsewhere.6, 59, 61 The recent recommendations of the American Society of Echocardiography on quantification methods in pediatric echocardiography concluded that standardizing quantification methods is the first step in the task of generating a normative database that encompasses the range of body

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