Abstract
BackgroundInherited metabolic diseases (IMDs) are a group of individually rare single-gene diseases. For many IMDs, there is a paucity of high-quality evidence that evaluates the effectiveness of clinical interventions. Clinical effectiveness trials of IMD interventions could be supported through the development of core outcome sets (COSs), a recommended minimum set of standardized, high-quality outcomes and associated outcome measurement instruments to be incorporated by all trials in an area of study. We began the process of establishing pediatric COSs for two IMDs, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency and phenylketonuria (PKU), by reviewing published literature to describe outcomes reported by authors, identify heterogeneity in outcomes across studies, and assemble a candidate list of outcomes.MethodsWe used a comprehensive search strategy to identify primary studies and guidelines relevant to children with MCAD deficiency and PKU, extracting study characteristics and outcome information from eligible studies including outcome measurement instruments for select outcomes. Informed by an established framework and a previously published pediatric COS, outcomes were grouped into five, mutually-exclusive, a priori core areas: growth and development, life impact, pathophysiological manifestations, resource use, and death.ResultsFor MCAD deficiency, we identified 83 outcomes from 52 articles. The most frequently represented core area was pathophysiological manifestations, with 33 outcomes reported in 29/52 articles (56%). Death was the most frequently reported outcome. One-third of outcomes were reported by a single study. The most diversely measured outcome was cognition and intelligence/IQ for which eight unique measurement instruments were reported among 14 articles. For PKU, we identified 97 outcomes from 343 articles. The most frequently represented core area was pathophysiological manifestations with 31 outcomes reported in 281/343 articles (82%). Phenylalanine concentration was the most frequently reported outcome. Sixteen percent of outcomes were reported by a single study. Similar to MCAD deficiency, the most diversely measured PKU outcome was cognition and intelligence/IQ with 39 different instruments reported among 82 articles.ConclusionsHeterogeneity of reported outcomes and outcome measurement instruments across published studies for both MCAD deficiency and PKU highlights the need for COSs for these diseases, to promote the use of meaningful outcomes and facilitate comparisons across studies.
Highlights
Inherited metabolic diseases (IMDs) are a group of individually rare single-gene diseases
Heterogeneity of reported outcomes and outcome measurement instruments across published studies for both medium-chain acyl-CoA dehydrogenase (MCAD) deficiency and PKU highlights the need for Core Outcome Set (COS) for these diseases, to promote the use of meaningful outcomes and facilitate comparisons across studies
Due to time restraints and the large number of studies that were eligible for PKU, we decided to limit the initial data extraction for articles retrieved in the PKU search to only those that were published in the year 2001 or more recently; we reviewed outcomes from studies from each previous year in turn, starting with 2000, until no new unique outcomes for PKU were identified
Summary
Inherited metabolic diseases (IMDs) are a group of individually rare single-gene diseases. Clinical effectiveness trials of IMD interventions could be supported through the development of core outcome sets (COSs), a recommended minimum set of standardized, high-quality outcomes and associated outcome measurement instruments to be incorporated by all trials in an area of study. Trials have not always focused on those outcomes that are most relevant to patients diagnosed with the diseases being studied [6], and different trials within a single area of research have often incorporated disparate outcomes and outcome measurement instruments, impeding comparisons among studies and limiting capacity for data synthesis [7] In response to these challenges, the Core Outcome Measures in Effectiveness Trials (COMET) Initiative [8] has led researchers in many disease areas to develop core outcome sets (COSs) [7]. Development and uptake of COSs aim to ensure that results can be synthesized and compared across studies
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