A systematic review of the assessment of the clinical utility of genomic sequencing: Implications of the lack of standard definitions and measures of clinical utility.

PURPOSE: Exome sequencing (ES) and genome sequencing (GS) are diagnostic tests for rare genetic diseases. Studies report clinical utility of ES/GS. The goal of this systematic review is to establish how clinical utility is defined and measured in studies evaluating the impacts of ES/GS results for pediatric patients. METHODS: Relevant articles were identified in PubMed, Medline, Embase, and Web of Science. Eligible studies assessed clinical utility of ES/GS for pediatric patients published before 2021. Other relevant articles were added based on articles' references. Articles were coded to assess definitions and measures of clinical utility. RESULTS: Of 1346 articles, 83 articles met eligibility criteria. Clinical utility was not clearly defined in 19% of studies and 92% did not use an explicit measure of clinical utility. When present, definitions of clinical utility diverged from recommended definitions and varied greatly, from narrow (diagnostic yield of ES/GS) to broad (including decisions about withdrawal of care/palliative care and/or impacts on other family members). CONCLUSION: Clinical utility is used to guide policy and practice decisions about test use. The lack of a standard definition of clinical utility of ES/GS may lead to under- or overestimations of clinical utility, complicating policymaking and raising ethical issues.

Noninvasive Prenatal Testing: Views of Canadian Pregnant Women and Their Partners Regarding Pressure and Societal Concerns.

BACKGROUND: Noninvasive prenatal testing (NIPT) provides important benefits yet raises ethical concerns. We surveyed Canadian pregnant women and their partners to explore their views regarding pressure to test and terminate a pregnancy, as well as other societal impacts that may result from the routinization of NIPT. METHODS: A questionnaire was offered (March 2015 to July 2016) to pregnant women and their partners at five healthcare facilities in four Canadian provinces. RESULTS: 882 pregnant women and 395 partners completed the survey. 64% of women anticipated feeling no pressure to take the test if it were offered routinely, and 39% were not concerned about routinization leading to increased pressure to terminate a pregnancy of a fetus with Down Syndrome. Regarding other social concerns possibly resulting from routinization, pregnant women were most concerned regarding a reduction in resources available for people with Down Syndrome and their families and least concerned regarding a decrease in the population of people with Down Syndrome. CONCLUSIONS: Our findings reflect the concerns expressed by pregnant women and their partners, both personal (pressure to test, pressure to terminate) and societal (e.g., regarding potential negative impact on people with disabilities and their families). Even if most women were not concerned about feeling pressured to test due to NIPT routinization, a large minority express concerns that should not be taken lightly. Moreover, a majority of respondents were concerned regarding pressure to terminate pregnancies due to NIPT routinization as well as regarding most societal impacts they were queried on, especially the possible future reduction in resources available for people with DS and their families. Canadian policy-makers should consider these potential negative ramifications of NIPT and ensure that appropriate social policies accompany its implementation.

Implementation science as a leadership capability to improve patient outcomes and value in healthcare.

When evidence thresholds are met, adopting healthcare innovations should add value, and this is forgone when evidence is not translated into practice. Activities that are not supported by evidence lead to ineffective or unnecessary care, or harm, poor outcomes, and low-value healthcare. This article provides an overview of implementation science, which is the scientific study of why implementation succeeds or fails. We draw parallels between the LEADS in a Caring Environment leadership framework and implementation science process models and frameworks. Taken together, the principles and practices in LEADS and the aims of implementation science are effectively quite similar and can be useful for healthcare management looking to optimize resources when implementing evidence-based practice and innovation into routine clinical care.

The value of non-invasive prenatal testing: preferences of Canadian pregnant women, their partners, and health professionals regarding NIPT use and access.

BACKGROUND: Canadian policies regarding the implementation and public coverage of non-invasive prenatal testing (NIPT) are heterogeneous and shifting, with NIPT being publicly covered for high-risk pregnancies in some provinces, but not others. Such a diverse and evolving policy landscape provides fertile ground for examining the preferences of pregnant women, their partners, and health professionals regarding the implementation and coverage of NIPT by the public healthcare system, as well as the factors influencing their preferences, which is what the present study does. METHODS: In this paper, we report the results of three-large scale Canadian surveys, in which 882 pregnant women, 395 partners of pregnant women, and 184 healthcare professionals participated. RESULTS: The paper focuses on preferences regarding how and when NIPT should be used, as well as the factors influencing these preferences, and how coverage for NIPT should be provided. These are correlated with respondents' levels of knowledge about Down syndrome and testing technologies and with their stated intended use of NIPT results. CONCLUSION: Salient is the marked difference between the preferences of prospective parents and those of healthcare professionals, which has potential implications for Canadian policy regarding NIPT implementation and insurance coverage.

Pre-implantation Genetic Diagnosis: The Road Forward in Canada.

The use of pre-implantation genetic diagnosis (PGD) is increasing as the list of indications it can test for constantly expands. This raises new challenges for clinicians and prospective parents regarding possible uses and calls for guidance. Policy approaches towards PGD vary greatly worldwide. The 2004 Canadian Assisted Human Reproduction Act does not provide guidance, except for prohibiting non-medical sex selection. Criminal legislation is an unsuitable policy instrument to regulate human genetics and reproductive medicine. We call for professional societies to issue guidelines regarding the uses of PGD that would establish the standard of care and legal norms. Such guidelines should be based on a patient-centered approach and respect individual autonomy in reproductive decision-making. Canadian approaches to PGD should also consider issues related to equity of access. Moreover, since PGD often raises concerns about eugenic uses, guidelines should also consider its societal impact and its implementation should be accompanied by policies that maintain or increase social support for people with disabilities. Finally, public engagement could provide an evidence-base regarding Canadian societal values and concerns that should guide regulatory reform, for example, the regulation of non-medical sex selection through PGD.

The health system impact of false positive newborn screening results for medium-chain acyl-CoA dehydrogenase deficiency: a cohort study.

BACKGROUND: There is no consensus in the literature regarding the impact of false positive newborn screening results on early health care utilization patterns. We evaluated the impact of false positive newborn screening results for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) in a cohort of Ontario infants. METHODS: The cohort included all children who received newborn screening in Ontario between April 1, 2006 and March 31, 2010. Newborn screening and diagnostic confirmation results were linked to province-wide health care administrative datasets covering physician visits, emergency department visits, and inpatient hospitalizations, to determine health service utilization from April 1, 2006 through March 31, 2012. Incidence rate ratios (IRRs) were used to compare those with false positive results for MCADD to those with negative newborn screening results, stratified by age at service use. RESULTS: We identified 43 infants with a false positive newborn screening result for MCADD during the study period. These infants experienced significantly higher rates of physician visits (IRR: 1.42) and hospitalizations (IRR: 2.32) in the first year of life relative to a screen negative cohort in adjusted analyses. Differences in health services use were not observed after the first year of life. CONCLUSIONS: The higher use of some health services among false positive infants during the first year of life may be explained by a psychosocial impact of false positive results on parental perceptions of infant health, and/or by differences in underlying health status. Understanding the impact of false positive newborn screening results can help to inform newborn screening programs in designing support and education for families. This is particularly important as additional disorders are added to expanded screening panels, yielding important clinical benefits for affected children but also a higher frequency of false positive findings.

Motivating factors for physician ordering of factor V Leiden genetic tests.

BACKGROUND: The factor V Leiden (FVL) genetic test is used by many physicians despite its uncertain clinical utility. METHODS: We investigate whether self-reported motivations and behaviors concerning FVL genetic testing differ between 2 groups of primary care physicians defined by frequency of previous FVL test use. In January 2007, 112 physicians (60 frequent and 52 infrequent FVL test users) at Group Health, a large health care delivery system, were surveyed. Survey content areas included primary reasons and motivating factors for ordering the FVL test, the likelihood of ordering the FVL test for hypothetical patients, potential barriers to genetic testing, and practices and skills regarding FVL test ordering. RESULTS: Responses between groups agreed concerning most clinical- and patient-related factors. Frequent-FVL physicians were more likely than infrequent-FVL physicians to report ordering the FVL test for hypothetical patients with mesenteric venous thrombosis (adjusted odds ratio, 4.57; 95% confidence interval, 1.55-13.53) or venous thrombosis after hospital discharge (adjusted odds ratio, 3.42; 95% confidence interval, 1.30-8.95). Frequent-FVL physicians were also less likely to identify several items on the survey as barriers to genetic testing and were more likely to report high confidence in interpreting and explaining FVL test results. CONCLUSIONS: Generally, both physician groups reported similar motivating factors for ordering FVL tests, and reported behaviors were consistent with existing guidelines. More striking differences were observed for measures such as barriers to and confidence in using genetic tests. Although additional research is necessary to evaluate the impact of these results, they inform several knowledge-to-practice translation issues that are important for the successful integration of genetic testing into primary care.