Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study

Abstract Background The use of proactive genetic screening for disease prevention and early detection is not yet widespread. Professional practice guidelines from the American College of Medical Genetics and Genomics (ACMG) have encouraged reporting pathogenic variants that confer personal risk for actionable monogenic hereditary disorders, but only as secondary findings from exome or genome sequencing. The Centers for Disease Control and Prevention (CDC) recognizes the potential public health impact of three Tier 1 actionable disorders. Here, we report results of a large multi-center cohort study to determine the yield and potential value of screening healthy individuals for variants associated with a broad range of actionable monogenic disorders, outside the context of secondary findings. Methods Eligible adults were offered a proactive genetic screening test by health care providers in a variety of clinical settings. The screening panel based on next-generation sequencing contained up to 147 genes associated with monogenic disorders within cancer, cardiovascular, and other important clinical areas. Sequence and intragenic copy number variants classified as pathogenic, likely pathogenic, pathogenic (low penetrance), or increased risk allele were considered clinically significant and reported. Results were analyzed by clinical area and severity/burden of disease using chi-square tests without Yates’ correction. Results Among 10,478 unrelated adults screened, 1619 (15.5%) had results indicating personal risk for an actionable monogenic disorder. In contrast, only 3.1 to 5.2% had clinically reportable variants in genes suggested by the ACMG version 2 secondary findings list to be examined during exome or genome sequencing, and 2% had reportable variants related to CDC Tier 1 conditions. Among patients, 649 (6.2%) were positive for a genotype associated with a disease of high severity/burden, including hereditary cancer syndromes, cardiovascular disorders, or malignant hyperthermia susceptibility. Conclusions This is one of the first real-world examples of specialists and primary care providers using genetic screening with a multi-gene panel to identify health risks in their patients. Nearly one in six individuals screened for variants associated with actionable monogenic disorders had clinically significant results. These findings provide a foundation for further studies to assess the role of genetic screening as part of regular medical care.

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Correction to: Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study

BMC Medicine ◽

10.1186/s12916-021-02141-y ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Eden V. Haverfield ◽

Edward D. Esplin ◽

Sienna J. Aguilar ◽

Kathryn E. Hatchell ◽

Kelly E. Ormond ◽

...

Keyword(s):

Cohort Study ◽

Genetic Screening ◽

Personal Risk

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Exome and genome sequencing in adults with undiagnosed disease: a prospective cohort study

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-106936 ◽

2020 ◽

pp. jmedgenet-2020-106936

Author(s):

Salma Shickh ◽

Mariana Gutierrez Salazar ◽

Kathleen-Rose Zakoor ◽

Conxi Lázaro ◽

Jessica Gu ◽

...

Keyword(s):

Cohort Study ◽

Genome Sequencing ◽

Prospective Cohort Study ◽

Prospective Cohort ◽

Cancer Genetics ◽

Diagnostic Yield ◽

Diagnostic Utility ◽

Secondary Findings ◽

Cancer History ◽

Genetic Test Results

BackgroundExome and genome sequencing have been demonstrated to increase diagnostic yield in paediatric populations, improving treatment options and providing risk information for relatives. There are limited studies examining the clinical utility of these tests in adults, who currently have limited access to this technology.MethodsPatients from adult and cancer genetics clinics across Toronto, Ontario, Canada were recruited into a prospective cohort study evaluating the diagnostic utility of exome and genome sequencing in adults. Eligible patients were ≥18 years of age and suspected of having a hereditary disorder but had received previous uninformative genetic test results. In total, we examined the diagnostic utility of exome and genome sequencing in 47 probands and 34 of their relatives who consented to participate and underwent exome or genome sequencing.ResultsOverall, 17% (8/47) of probands had a pathogenic or likely pathogenic variant identified in a gene associated with their primary indication for testing. The diagnostic yield for patients with a cancer history was similar to the yield for patients with a non-cancer history (4/18 (22%) vs 4/29 (14%)). An additional 24 probands (51%) had an inconclusive result. Secondary findings were identified in 10 patients (21%); three had medically actionable results.ConclusionsThis study lends evidence to the diagnostic utility of exome or genome sequencing in an undiagnosed adult population. The significant increase in diagnostic yield warrants the use of this technology. The identification and communication of secondary findings may provide added value when using this testing modality as a first-line test.

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754 Insomnia and Depression Symptoms in Primary Care Patients Referred for Mental Health Care

SLEEP ◽

10.1093/sleep/zsab072.751 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A294-A294

Author(s):

Ivan Vargas ◽

Alexandria Muench ◽

Mark Seewald ◽

Cecilia Livesey ◽

Matthew Press ◽

...

Keyword(s):

Mental Health ◽

Primary Care ◽

Health Care ◽

Mental Health Care ◽

Primary Care Providers ◽

Depression Symptoms ◽

Care Providers ◽

Mild Depression ◽

Significant Depression ◽

Clinically Significant

Abstract Introduction Past epidemiological research indicates that insomnia and depression are both highly prevalent and tend to co-occur in the general population. The present study further assesses this association by estimating: (1) the concurrence rates of insomnia and depression in outpatients referred by their primary care providers for mental health care; and (2) whether the association between depression and insomnia varies by insomnia subtype (initial, middle, and late). Methods Data were collected from 3,174 patients (mean age=42.7; 74% women; 50% Black) who were referred to the integrated care program for assessment of mental health symptoms (2018–2020). All patients completed an Insomnia Severity Index (ISI) and a Patient Health Questionnaire (PHQ-9) during their evaluations. Total scores for the ISI and PHQ-9 were computed. These scores were used to categorize patients into diagnostic groups for insomnia (no-insomnia [ISI < 8], subthreshold-insomnia [ISI 8–14], and clinically-significant-insomnia [ISI>14]) and depression (no-depression [PHQ-914]). Items 1–3 of the ISI were also used to assess the association between depression and subtypes of insomnia. Results Rates of insomnia were as follows: 34.6% for subthreshold-insomnia, 35.5% for clinically-significant insomnia, and 28.9% for mild-depression and 26.9% for clinically-significant-depression. 92% of patients with clinically significant depression reported at least subthreshold levels of insomnia. While the majority of patients with clinical depression reported having insomnia, the proportion of patients that endorsed these symptoms were comparable across insomnia subtypes (percent by subtype: initial insomnia 63%; middle insomnia 61%; late insomnia 59%). Conclusion According to these data, the proportion of outpatients referred for mental health evaluations that endorse treatable levels of insomnia is very high (approximately 70%). This naturally gives rise to at least two questions: how will such symptomatology be addressed (within primary or specialty care) and what affect might targeted treatment for insomnia have on health were it a focus of treatment in general? Support (if any) Vargas: K23HL141581; Perlis: K24AG055602

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Evaluation of a multidisciplinary lipid clinic to improve the care of individuals with severe lipid conditions: a RE-AIM framework analysis

Implementation Science Communications ◽

10.1186/s43058-021-00135-8 ◽

2021 ◽

Vol 2 (1) ◽

Author(s):

Laney K. Jones ◽

Megan McMinn ◽

David Kann ◽

Michael Lesko ◽

Amy C. Sturm ◽

...

Keyword(s):

Primary Care ◽

Program Effectiveness ◽

Primary Care Providers ◽

Care Providers ◽

Lipid Levels ◽

Framework Analysis ◽

Lipid Clinic ◽

Adherence Counseling ◽

Clinically Significant

Abstract Background Individuals with complex dyslipidemia, or those with medication intolerance, are often difficult to manage in primary care. They require the additional attention, expertise, and adherence counseling that occurs in multidisciplinary lipid clinics (MDLCs). We conducted a program evaluation of the first year of a newly implemented MDLC utilizing the RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) framework to provide empirical data not only on program effectiveness, but also on components important to local sustainability and future generalizability. Methods The purpose of the MDLC is to increase the uptake of guideline-based care for lipid conditions. Established in 2019, the MDLC provides care via a centralized clinic location within the healthcare system. Primary care providers and cardiologists were invited to refer individuals with lipid conditions. Using a pre/post-study design, we evaluated the implementation outcomes from the MDLC using the RE-AIM framework. Results In 2019, 420 referrals were made to the MDLC (reach). Referrals were made by 19% (148) of the 796 active cardiology and primary care providers, with an average of 35 patient referrals per month in 2019 (SD 12) (adoption). The MDLC saw 83 patients in 2019 (reach). Additionally, 50% (41/82) had at least one follow-up MDLC visit, and 12% (10/82) had two or more follow-up visits in 2019 (implementation). In patients seen by the MDLC, we found an improved diagnosis of specific lipid conditions (FH (familial hypercholesterolemia), hypertriglyceridemia, and dyslipidemia), increased prescribing of evidence-based therapies, high rates of medication prior authorization approvals, and significant reductions in lipid levels by lipid condition subgroup (effectiveness). Over time, the operations team decided to transition from in-person follow-up to telehealth appointments to increase capacity and sustain the clinic (maintenance). Conclusions Despite limited reach and adoption of the MDLC, we found a large intervention effect that included improved diagnosis, increased prescribing of guideline-recommended treatments, and clinically significant reduction of lipid levels. Attention to factors including solutions to decrease the large burden of unseen referrals, discussion of the appropriate number and duration of visits, and sustainability of the clinic model could aid in enhancing the success of the MDLC and improving outcomes for more patients throughout the system.

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The incidence and prevalence of inflammatory bowel disease in UK primary care: a retrospective cohort study of the IQVIA Medical Research Database

BMC Gastroenterology ◽

10.1186/s12876-021-01716-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Karoline Freeman ◽

Ronan Ryan ◽

Nicholas Parsons ◽

Sian Taylor-Phillips ◽

Brian H. Willis ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

General Practice ◽

Cohort Study ◽

Medical Research ◽

Bowel Disease ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

Research Database ◽

Care Providers ◽

Inflammatory Bowel

Abstract Background Our knowledge of the incidence and prevalence of inflammatory bowel disease (IBD) is uncertain. Recent studies reported an increase in prevalence. However, they excluded a high proportion of ambiguous cases from general practice. Estimates are needed to inform health care providers who plan the provision of services for IBD patients. We aimed to estimate the IBD incidence and prevalence in UK general practice. Methods We undertook a retrospective cohort study of routine electronic health records from the IQVIA Medical Research Database covering 14 million patients. Adult patients from 2006 to 2016 were included. IBD was defined as an IBD related Read code or record of IBD specific medication. Annual incidence and 12-month period prevalence were calculated. Results The prevalence of IBD increased between 2006 and 2016 from 106.2 (95% CI 105.2–107.3) to 142.1 (95% CI 140.7–143.5) IBD cases per 10,000 patients which is a 33.8% increase. Incidence varied across the years. The incidence across the full study period was 69.5 (95% CI 68.6–70.4) per 100,000 person years. Conclusions In this large study we found higher estimates of IBD incidence and prevalence than previously reported. Estimates are highly dependent on definitions of disease and previously may have been underestimated.

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The effects of weight fluctuation on the components of metabolic syndrome: a 16-year prospective cohort study in South Korea

Archives of Public Health ◽

10.1186/s13690-021-00539-x ◽

2021 ◽

Vol 79 (1) ◽

Author(s):

Young Ran Chin ◽

Eun Sun So

Keyword(s):

Metabolic Syndrome ◽

Cohort Study ◽

Prospective Cohort Study ◽

Abdominal Obesity ◽

Prospective Cohort ◽

Weight Control ◽

Normal Weight ◽

Health Concern ◽

Care Providers ◽

Weight Fluctuation

Abstract Background Weight fluctuation (WF) is highly prevalent in parallel with the high prevalence of intentional or unintentional dieting. The health risks of frequent WF for metabolic syndrome (MS) have become a public health concern, especially for health care providers who supervise dieting as an intervention to prevent obesity-related morbidity or to improve health, as well as for the general population for whom dieting is of interest. The aim of this study was to investigate the long-term effect of WF on the risk of MS in Koreans. Methods This study analyzed secondary data from the Korean Genome and Epidemiology Study, a 16-year prospective cohort study, on 8150 individuals using time-dependent Cox regression. Results WF did not increase the risk of MS in either normal-weight or obese subjects. In an analysis of the components of MS, greater WF significantly increased the risk of abdominal obesity (HR = 1.05, 95% CI = 1.02–1.07, p < 0.001) in normal-weight individuals. However, WF did not increase the risk of hyperglycemia, low high-density lipoprotein cholesterol levels, elevated blood pressure, or raised fasting glucose in normal-weight individuals, and it did not influence any of the components of MS in obese individuals. Conclusion Since WF was found to be a risk factor for abdominal obesity, which is the most reliable predictor of MS, it should be considered when addressing weight control. Further studies on cut-off points for the degree of weight loss in a certain period need to be conducted to help clinicians provide guidance on appropriate weight control.

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Prescribing and testing by primary care providers to assess adherence to the Choosing Wisely Canada recommendations: a retrospective cohort study

CMAJ Open ◽

10.9778/cmajo.20180053 ◽

2018 ◽

Vol 6 (4) ◽

pp. E603-E610

Author(s):

Alexander Singer ◽

Leanne Kosowan ◽

Alan Katz ◽

Kheira Jolin-Dahel ◽

Karen Appel ◽

...

Keyword(s):

Primary Care ◽

Cohort Study ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

Primary Care Providers ◽

Choosing Wisely ◽

Care Providers

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MBRS-59. SINGLE-CELL WHOLE-GENOME SEQUENCING DISSECTS INTRA-TUMOURAL GENOMIC HETEROGENEITY AND CLONAL EVOLUTION IN CHILDHOOD MEDULLOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.563 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii408-iii408

Author(s):

Marina Danilenko ◽

Masood Zaka ◽

Claire Keeling ◽

Stephen Crosier ◽

Rafiqul Hussain ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Single Cell ◽

Genome Sequencing ◽

Copy Number ◽

Single Cell Analysis ◽

Mutational Analysis ◽

Single Cells ◽

Clonal Evolution ◽

Whole Genome ◽

Clinically Significant

Abstract Medulloblastomas harbor clinically-significant intra-tumoral heterogeneity for key biomarkers (e.g. MYC/MYCN, β-catenin). Recent studies have characterized transcriptional heterogeneity at the single-cell level, however the underlying genomic copy number and mutational architecture remains to be resolved. We therefore sought to establish the intra-tumoural genomic heterogeneity of medulloblastoma at single-cell resolution. Copy number patterns were dissected by whole-genome sequencing in 1024 single cells isolated from multiple distinct tumour regions within 16 snap-frozen medulloblastomas, representing the major molecular subgroups (WNT, SHH, Group3, Group4) and genotypes (i.e. MYC amplification, TP53 mutation). Common copy number driver and subclonal events were identified, providing clear evidence of copy number evolution in medulloblastoma development. Moreover, subclonal whole-arm and focal copy number alterations covering important genomic loci (e.g. on chr10 of SHH patients) were detected in single tumour cells, yet undetectable at the bulk-tumor level. Spatial copy number heterogeneity was also common, with differences between clonal and subclonal events detected in distinct regions of individual tumours. Mutational analysis of the cells allowed dissection of spatial and clonal heterogeneity patterns for key medulloblastoma mutations (e.g. CTNNB1, TP53, SMARCA4, PTCH1) within our cohort. Integrated copy number and mutational analysis is underway to establish their inter-relationships and relative contributions to clonal evolution during tumourigenesis. In summary, single-cell analysis has enabled the resolution of common mutational and copy number drivers, alongside sub-clonal events and distinct patterns of clonal and spatial evolution, in medulloblastoma development. We anticipate these findings will provide a critical foundation for future improved biomarker selection, and the development of targeted therapies.

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Quality of solo ambulance care by physician assistants versus ambulance nurses for non-conveyed patients in the Netherlands: An observational study

F1000Research ◽

10.12688/f1000research.51745.1 ◽

2021 ◽

Vol 10 ◽

pp. 357

Author(s):

Lilian Vloet ◽

Daniël Winterink ◽

Aico Gerritsen ◽

Wim Heutz ◽

Thijs van Zonneveld ◽

...

Keyword(s):

Patient Experience ◽

Emergency Care ◽

Physician Assistants ◽

Care Process ◽

Care Providers ◽

Follow Up Care ◽

Clinically Significant ◽

And Behavior ◽

Ambulance Nurse

Background The aim of this study was to compare the ambulance care process, follow-up care and patient experience between physician assistants and ambulance nurses operating as solo ambulance care providers, for a non-conveyed patient population. Methods An observational design was used. Characteristics of patients and events and the care process were retrieved from the ambulance registration database. Data on follow-up care and patient experience were collected through questionnaires. Results Of the included solo ambulance events, 49/379 (12.9%) were performed by physician assistants, 330/379 (87.1%) were performed by ambulance nurses. For initial complaints and the on-scene diagnoses there were no significant differences between the physician assistants and ambulance nurses. 90/165 (54.5%) of the patients requested follow-up care after being non-conveyed with no significant association between the PA and ambulance nurse group (p=.293). For type of follow-up care, 91.9% of the follow-up emergency care requests in this study came from patients treated by an ambulance nurse. There were no significant differences in patients’ experience for clinician attitude and behavior, treatment, and communication between physician assistants and ambulance nurses, although pain management and explanation about the non-conveyance decision could be improved Conclusions Besides small statistical but not clinically significant differences, this study indicated comparable solo ambulance care provided by a physician assistant or an ambulance nurse concerning the care process, follow-up care and patient experience. Patients treated by physician assistants seek less follow-up emergency care after non-conveyance, compared to ambulance nurses. Overall, patients experienced good attitude and behavior, treatment, and communication of the solo ambulance professional. Future well powered studies to gain insight in effects of PAs in ambulance care are needed, as well as studies in which PAs apply all additional skills they are licensed to.

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