Secondary findings from whole-exome/genome sequencing evaluating stakeholder perspectives. A review of the literature.

With the development of next generation sequencing, beyond identifying the cause of manifestations that justified prescription of the test, other information with potential interest for patients and their families, defined as secondary findings (SF), can be provided once patients have given informed consent, in particular when therapeutic and preventive options are available. The disclosure of such findings has caused much debate. The aim of this work was to summarize all opinion-based studies focusing on SF, so as to shed light on the concerns that this question generate. A review of the literature was performed, focusing on all PubMed articles reporting qualitative, quantitative or mixed studies that interviewed healthcare providers, participants, or society regarding this subject. The methodology was carefully analysed, in particular whether or not studies made the distinction between actionable and non-actionable SF, in a clinical or research context. From 2010 to 2016, 39 articles were compiled. A total of 14,868 people were interviewed (1259 participants, 6104 healthcare providers, 7505 representatives of society). When actionable and non-actionable SF were distinguished (20 articles), 92% of respondents were keen to have results regarding actionable SF (participants: 88%, healthcare providers: 86%, society: 97%), against 70% (participants: 83%, healthcare providers: 62%, society: 73%) for non-actionable SF. These percentages were slightly lower in the specific situation of children probands. For respondents, the notion of the «patient's choice¼ is crucial. For healthcare providers, the importance of defining policies for SF among diagnostic lab, learning societies and/or countries is outlined, in particular regarding the content and extension of the list of actionable genes to propose, the modalities of information, and the access to information about adult-onset diseases in minors. However, the existing literature should be taken with caution, since most articles lack a clear definition of SF and actionability, and referred to hypothetical scenarios with limited information to respondents. Studies conducted by multidisciplinary teams involving patients with access to results are sadly lacking, in particular in the medium term after the results have been given. Such studies would feed the debate and make it possible to measure the impact of such findings and their benefit-risk ratio.

[Changes in clinical practice related to the arrival of next-generation sequencing in the genetic diagnosis of developmental diseases]. / Les modifications de pratique clinique liées à l'arrivée du séquençage haut débit dans le diagnostic génétique des maladies du développement.

INTRODUCTION: The arrival of high-throughput sequencing (HTS) has led to a sweeping change in the diagnosis of developmental abnormalities (DA) with or without intellectual deficiency (ID). With the prospect of deploying these new technologies, two questions have been raised: the representations of HTS among geneticists and the costs incurred due to these analyses. METHODS: Geneticists attending a clinical genetics seminar were invited to complete a questionnaire. The statistical analysis was essentially descriptive and an analysis of costs was undertaken. RESULTS: Of those responding to the questionnaire, 48% had already prescribed exome analysis and 25% had already had the occasion to disclose the results of such analyses. Ninety-six percent were aware that whole-exome sequencing (WES) had certain limits and 74% expressed misgivings concerning its use in medical practice. In parallel, the evaluation of costs showed that WES was less expensive than conventional procedures. DISCUSSION: The survey revealed that geneticists had already come to terms with HTS as early as 2015. Among the major concerns expressed were the complexity of interpreting these tests and the many ethical implications. Geneticists seemed to be aware of the advantages but also the limits of these new technologies. The cost analysis raises questions about the place of HTS and in particular WES in the diagnostic work-up: should it be used early to obtain an etiological diagnosis rather than as the last resort? CONCLUSION: It is essential for future generations of doctors and for the families concerned to learn about the concepts of HTS, which is set to become a major feature of new genomic medicine.

The Mini Nutritional Assessment-Short Form and mortality in nursing home residents--results from the INCUR study.

OBJECTIVES: To examine whether the Mini Nutritional Assessment-Short Form (MNA-SF) score and its individual items are predictors of mortality in a nursing home population. DESIGN: Prospective, secondary analysis from the Incidence of pNeumonia and related ConseqUences in nursing home Residents (INCUR) study with 1-year follow-up. PARTICIPANTS: A total of 773 older persons (women 74.4%) living in 13 French nursing homes. MEASUREMENTS: At baseline, nutritional status was assessed with the MNA-SF. Overall mortality rate was measured over a 12-month follow-up period after the baseline assessment visit. Cox proportional hazard models were performed to test the predictive capacity of the MNA-SF score and its single components for mortality. RESULTS: Mean age of participants was 86.2 (standard deviation, SD 7.5) years. Mean MNA-SF score was 9.8 (SD 2.4). Among participants, 198 (25.6%) presented a normal nutritional status (12-14 points), 454 (58.7%) were at risk of malnutrition (8-11 points), and 121 (15.7%) were malnourished. After one year of follow-up, 135 (17.5%) participants had died. Age, female gender, baseline weight, BMI and MNA-SF were significant predictors of mortality whereas no specific chronic disease was. The total MNA-SF score was a significant predictor of mortality (Hazard Ratio=0.83; 95% CI 0.75-0.91; p<0.001), even after adjustment for potential confounders. Four individual items: weight loss, decrease in food intake, recent stress and BMI were independent predictors of mortality. CONCLUSIONS: The MNA-SF appears to be an accurate predictor of one-year mortality in nursing home residents. Thus, this tool may be regarded not only as a nutritional screening tool, but also as an instrument for identifying the most-at-risk individuals in this population.

Frailty Detection with the Gérontopôle Frailty Screening Tool (GFST).

Frailty is commonly regarded as a pre-disability condition of older persons. Its importance in the elderly should be more carefully taken into account in the clinical practice. To implement interventions aimed at preventing disability in frail older adults, screening tools for the early detection of this syndrome are needed. In this context, the Gérontopôle Frailty Screening Tool (GFST) has been recently proposed as an instrument for assisting general practitioners in the detection of non-disabled frail older adults. In the present paper, we briefly discuss about the difficulties of translating knowledge from the frailty research field to the clinical practice. Such difficulties are illustrated by presenting the evolution of the GFST over time. The use of frailty screening tools, such as the GFST, in the clinical practice is necessary to support the identification of older persons at risk of adverse events and promote the implementation of individualized strategies against disability.

Prevalence of Frailty and Mobility Limitation in a Rural Setting in France.

BACKGROUND: The prevalence of frailty is variable according to the adopted operational definition, the tested population, and the setting where it is explored. OBJECTIVE: To estimate the prevalence of frailty and mobility disability in community-dwelling persons aged 60 years and older. DESIGN: Cross-sectional analyses. SETTING: The rural area of Labastide-Murat (France). PARTICIPANTS: All community-dwelling persons aged 60 years and older living in the area and answering to the study survey (n=572/1022). MEASUREMENTS: The study questionnaire included questions defining mobility disability (as ability to walk 400 meters and climb up 2 flights of stairs) and frailty (according to the FRAIL instrument and a modified version of the original definition proposed by Fried and colleagues). RESULTS: Mean age of participants was 72.4 years old. Mobility disability was reported by 47 (8.3%) participants. The sedentariness criterion of frailty was the most prevalent in the present population. Overall, according to the FRAIL instrument, 77.6%, 14.0%, and 8.3% could be defined as robust, pre-frail/frail, and disabled, respectively. When the alternative definition of frailty mirroring the definition proposed in the Cardiovascular Health Study was adopted, the prevalence of frailty increased and showed gender-specific differences (p=0.02). CONCLUSIONS: A relevant number of older persons living in rural areas experiences physical impairments and presents an increased risk for major negative health-related events. These results may support the ongoing clinical and research actions aimed at preventing the functional decline in elders.