Points to Consider in the Clinical Use of NGS Panels for Mitochondrial Disease: An Analysis of Gene Inclusion and Consent Forms

Mitochondrial next generation sequencing (NGS) panels offer single-step analysis of the numerous nuclear genes involved in the structure, function, and maintenance of mitochondria. However, the complexities of mitochondrial biology and genetics raise points for consideration in clinical use of these tests. To understand the current status of mitochondrial genetic testing, we assessed the gene offerings and consent forms of mitochondrial NGS panels available from seven US-based clinical laboratories. The NGS panels varied markedly in number of genes (101–1204 genes), and the proportion of genes causing “classic” mitochondrial diseases and their phenocopies ranged widely between labs (18 %–94 % of panel contents). All panels included genes not associated with classic mitochondrial diseases (6 %–28 % of panel contents), including genes causing adult-onset neurodegenerative disorders, cancer predisposition, and other genetic syndromes or inborn errors of metabolism. Five of the panels included genes that are not listed in OMIM to be associated with a disease phenotype (5 %–49 % of panel contents). None of the consent documents reviewed had options for patient preference regarding receipt of incidental findings. These findings raise points of discussion applicable to mitochondrial diagnostics, but also to the larger arenas of exome and genome sequencing, including the need to consider the boundaries between clinical and research testing, the necessity of appropriate informed consent, and the responsibilities of clinical laboratories and clinicians. Based on these findings, we recommend careful evaluation by laboratories of the genes offered on NGS panels, clear communication of the predicted phenotypes, and revised consent forms to allow patients to make choices about receiving incidental findings. We hope that our analysis and recommendations will help to maximize the considerable clinical utility of NGS panels for the diagnosis of mitochondrial disease.     

When to Use Broader Internalising and Externalising Subscales Instead of the Hypothesised Five Subscales on the Strengths and Difficulties Questionnaire (SDQ): Data from British Parents,Teachers and Children

The Strengths and Difficulties Questionnaire (SDQ) is a widely used child mental health questionnaire with five hypothesised subscales. There is theoretical and preliminary empirical support for combining the SDQ’s hypothesised emotional and peer subscales into an ‘internalizing’ subscale and the hypothesised behavioral and hyperactivity subscales into an ‘externalizing’ subscale (alongside the fifth prosocial subscale). We examine this using parent, teacher and youth SDQ data from a representative sample of 5–16 year olds in Britain (N = 18,222). Factor analyses generally supported second-order internalizing and externalizing factors, and the internalizing and externalizing subscales showed good convergent and discriminant validity across informants and with respect to clinical disorder. By contrast, discriminant validity was poorer between the emotional and peer subscales and between the behavioral, hyperactivity and prosocial subscales. This applied particularly to children with low scores on those subscales. We conclude that there are advantages to using the broader internalizing and externalizing SDQ subscales for analyses in low-risk samples, while retaining all five subscales when screening for disorder.     

Design and Evaluation of a Decision Aid for Inviting Parents to Participate in a Fragile X Newborn Screening Pilot Study

The major objectives of this project were to develop and evaluate a brochure to help parents make an informed decision about participation in a fragile X newborn screening study. We used an iterative development process that drew on principles of Informed Decision Making (IDM), stakeholder input, design expertise, and expert evaluation. A simulation study with 118 women examined response to the brochure. An independent review rated the brochure high on informational content, guidance, and values. Mothers took an average of 6.5 min to read it and scored an average of 91.1 % correct on a knowledge test. Most women rated the brochure as high quality and trustworthy. When asked to make a hypothetical decision about study participation, 61.9 % would agree to screening. Structural equation modeling showed that agreement to screening and decisional confidence were associated with perceived quality and trust in the brochure. Minority and white mothers did not differ in perceptions of quality or trust. We demonstrate the application of IDM in developing a study brochure. The brochure was highly rated by experts and consumers, met high standards for IDM, and achieved stated goals in a simulation study. The IDM provides a model for consent in research disclosing complicated genetic information of uncertain value.     

The Cognitive Interview for Use with Adults: An Empirical Test of an Alternative Mnemonic and of a Partial Protocol

Research showed that the four Cognitive Interview (CI) mnemonics used individually are unequally effective. We propose to test (i) their benefit when used within the same free recall phase and (ii) an original instruction, ‘guided peripheral focus’ (GPF). In two studies, 84 and 42 students were interviewed with Structured Interviews (SI), CIs or CI variations about a film viewed 1 week before. Results indicated that (i) if a CI variation with the GPF instead of the ‘perspective’ elicits more correct information than an SI or a CI, variations replacing the ‘perspective’ or the ‘order’ and ‘perspective’ with control instruction(s) do not; (ii) a partial CI integrating the ‘everything’, ‘context’ and GPF increases correct information compared with an SI, whereas the CI does not. We will discuss in which extent these results demonstrate the effectiveness of the ‘everything’, ‘context’ and ‘GPF’ and a potential lack of benefit of the ‘order’ and ‘perspective’. Copyright © 2011 John Wiley & Sons, Ltd.