Dangerous diagnostics? Regulatory reform in the genomic era

Molecular diagnostics are expanding rapidly yet many have not been externally evaluated. Kelly Holloway and colleagues identify failings in the regulatory system and report on recent efforts at refor

Health Canada needs to act on laboratory-developed diagnostics

An international exposé of flawed regulations for medical implants prompted Canada’s health minister to announce sweeping changes to the regulation of medical devices.1 Yet an important subset of medical devices remains outside the purview of this regulatory overhaul: laboratory-developed tests

Reflections on the Cost of Low-Cost Whole Genome Sequencing: Framing the Health Policy Debate

The cost of whole genome sequencing is dropping rapidly. There has been a great deal of enthusiasm about the potential for this technological advance to transform clinical care. Given the interest and significant investment in genomics, this seems an ideal time to consider what the evidence tells us about potential benefits and harms, particularly in the context of health care policy. The scale and pace of adoption of this powerful new technology should be driven by clinical need, clinical evidence, and a commitment to put patients at the centre of health care policy

Genetic determinants of disease severity in the myotonic dystrophy type 1 OPTIMISTIC cohort

To evaluate the role of genetic variation at the locus on symptomatic diversity in 250 adult, ambulant patients with myotonic dystrophy type 1 (DM1) recruited to the Observational Prolonged Trial in Myotonic Dystrophy Type 1 to Improve Quality of Life-Standards, a Target Identification Collaboration (OPTIMISTIC) clinical trial.We used small pool PCR to correct age at sampling biases and estimate the progenitor allele CTG repeat length and somatic mutational dynamics, and AciI digests and repeat primed PCR to test for the presence of variant repeats.We confirmed disease severity is driven by progenitor allele length, is further modified by age, and, in some cases, sex, and that patients in whom the CTG repeat expands more rapidly in the soma develop symptoms earlier than predicted. We revealed a key role for variant repeats in reducing disease severity and quantified their role in delaying age at onset by approximately 13.2 years (95% confidence interval 5.7-20.7, 2-tailed test = -3.7, = 0.0019).Careful characterization of the CTG repeat to define progenitor allele length and presence of variant repeats has increased utility in understanding clinical variability in a trial cohort and provides a genetic route for defining disease-specific outcome measures, and the basis of treatment response and stratification in DM1 trials

Associations Between Variant Repeat Interruptions and Clinical Outcomes in Myotonic Dystrophy Type 1

Objective: To assess the association between variant repeat (VR) interruptions in patients with myotonic dystrophy type 1 (DM1) and clinical symptoms and outcome measures after cognitive behavioral therapy (CBT) intervention. Methods: Adult patients with DM1 were recruited within the OPTIMISTIC trial (NCT02118779). Disease-related history, current clinical symptoms and comorbidities, functional assessments, and disease- and health-related questionnaires were obtained at baseline and after 5 and 10 months. After genetic analysis, we assessed the association between the presence of VR interruptions and clinical symptoms' long-term outcomes and compared the effects of CBT in patients with and without VR interruptions. Core trial outcome measures analyzed were: 6-minute walking test, DM1-Activ-C, Checklist Individual Strength Fatigue Score, Myotonic Dystrophy Health Index, McGill-Pain questionnaire, and Beck Depression inventory—fast screen. Blood samples for DNA testing were obtained at the baseline visit for determining CTG length and detection of VR interruptions. Results: VR interruptions were detectable in 21/250 patients (8.4%)—12 were assigned to the standard-of-care group (control group) and 9 to the CBT group. Patients with VR interruptions were significantly older when the first medical problem occurred and had a significantly shorter disease duration at baseline. We found a tendency toward a milder disease severity in patients with VR interruptions, especially in ventilation status, mobility, and cardiac symptoms. Changes in clinical outcome measures after CBT were not associated with the presence of VR interruptions. Conclusions: The presence of VR interruptions is associated with a later onset of the disease and a milder phenotype. However, based on the OPTIMISTIC trial data, the presence of VR interruptions was not associated with significant changes on outcome measures after CBT intervention. Trial Registration: Information ClinicalTrials.gov NCT02118779

Integrating cardiovascular diseases, hypertension, and diabetes with HIV services: a systematic review.

Non-communicable diseases (NCDs), including cardiovascular diseases (CVD), hypertension and diabetes together with HIV infection are among the major public health concerns worldwide. Health services for HIV and NCDs require health systems that provide for people's chronic care needs, which present an opportunity to coordinate efforts and create synergies between programs to benefit people living with HIV and/or AIDS and NCDs. This review included studies that reported service integration for HIV and/or AIDS with coronary heart diseases, chronic CVD, cerebrovascular diseases (stroke), hypertension or diabetes. We searched multiple databases from inception until October 2015. Articles were screened independently by two reviewers and assessed for risk of bias. 11,057 records were identified with 7,616 after duplicate removal. After screening titles and abstracts, 14 papers addressing 17 distinct interventions met the inclusion criteria. We categorized integration models by diseases (HIV with diabetes, HIV with hypertension and diabetes, HIV with CVD and finally HIV with hypertension and CVD and diabetes). Models also looked at integration from micro (patient focused integration) to macro (system level integrations). Most reported integration of hypertension and diabetes with HIV and AIDS services and described multidisciplinary collaboration, shared protocols, and incorporating screening activities into community campaigns. Integration took place exclusively at the meso-level, with no micro- or macro-level integrations described. Most were descriptive studies, with one cohort study reporting evaluative outcomes. Several innovative initiatives were identified and studies showed that CVD and HIV service integration is feasible. Integration should build on existing protocols and use the community as a locus for advocacy and health services, while promoting multidisciplinary teams, including greater involvement of pharmacists. There is a need for robust and well-designed studies at all levels - particularly macro-level studies, research looking at long-term outcomes of integration, and research in a more diverse range of countries

Interventions and approaches to integrating HIV and mental health services: a systematic review.

BACKGROUND: The frequency in which HIV and AIDS and mental health problems co-exist, and the complex bi-directional relationship between them, highlights the need for effective care models combining services for HIV and mental health. Here, we present a systematic review that synthesizes the literature on interventions and approaches integrating these services. METHODS: This review was part of a larger systematic review on integration of services for HIV and non-communicable diseases. Eligible studies included those that described or evaluated an intervention or approach aimed at integrating HIV and mental health care. We searched multiple databases from inception until October 2015, independently screened articles identified for inclusion, conducted data extraction, and assessed evaluative papers for risk of bias. RESULTS: Forty-five articles were eligible for this review. We identified three models of integration at the meso and micro levels: single-facility integration, multi-facility integration, and integrated care coordinated by a non-physician case manager. Single-site integration enhances multidisciplinary coordination and reduces access barriers for patients. However, the practicality and cost-effectiveness of providing a full continuum of specialized care on-site for patients with complex needs is arguable. Integration based on a collaborative network of specialized agencies may serve those with multiple co-morbidities but fragmented and poorly coordinated care can pose barriers. Integrated care coordinated by a single case manager can enable continuity of care for patients but requires appropriate training and support for case managers. Involving patients as key actors in facilitating integration within their own treatment plan is a promising approach. CONCLUSION: This review identified much diversity in integration models combining HIV and mental health services, which are shown to have potential in yielding positive patient and service delivery outcomes when implemented within appropriate contexts. Our review revealed a lack of research in low- and middle- income countries, and was limited to most studies being descriptive. Overall, studies that seek to evaluate and compare integration models in terms of long-term outcomes and cost-effectiveness are needed, particularly at the health system level and in regions with high HIV and AIDS burden

Asthma prescribing according to Arg16Gly beta-2 genotype: a randomised trial in adolescents

Introduction The A allele of rs1042713 (Arg16 amino acid) in the beta-2 (β2) adrenoreceptor is associated with poor response to long-acting β2-agonist (LABA) in young people with asthma. Our aim was to assess whether the prescribing of second line controller with LABA or a leukotriene receptor antagonist (LTRA) according to Arg16Gly genotype would result in improvements in pediatric asthma-related quality of life questionnaire (PAQLQ). Methods We performed a pragmatic randomised controlled trial (RCT) via a primary care clinical research network covering England and Scotland. We enrolled participants aged 12–18 years with asthma taking inhaled corticosteroids. A total of 241 participants (mean (sd) age 14.7 years (1.91)) were randomised (1:1) to receive personalised care (genotype directed prescribing) or standard guideline care. Following 4-week run-in participants were followed for 12-months. The primary outcome measure was change in PAQLQ. Asthma control, asthma exacerbation frequency and healthcare utilisation were secondary outcomes. Results Genotype directed prescribing resulted in an improvement in PAQLQ compared to standard care 0.16, (95%CI 0.00–0.31; p=0.049), although this improvement was below the pre-determined clinical threshold of 0.25. The AA genotype was associated with a larger improvement in PAQLQ with personalised versus standard care 0.42, (95%CI 0.02–0.81; p=0.041). Conclusion This is the first RCT demonstrating that genotype driven asthma prescribing is associated with a significant improvement in a clinical outcome compared to standard care. Adolescents with the AA homozygous genotype benefited most. The potential role of such β2-adrenoceptor genotype directed therapy in younger and more severe childhood asthma warrants further exploration

Half a Century of Wilson & Jungner: Reflections on the Governance of Population Screening.

Background: In their landmark report on the "Principles and Practice of Screening for Disease" (1968), Wilson and Jungner noted that the practice of screening is just as important for securing beneficial outcomes and avoiding harms as the formulation of principles. Many jurisdictions have since established various kinds of "screening governance organizations" to provide oversight of screening practice. Yet to date there has been relatively little reflection on the nature and organization of screening governance itself, or on how different governance arrangements affect the way screening is implemented and perceived and the balance of benefits and harms it delivers. Methods: An international expert policy workshop convened by Sturdy, Miller and Hogarth. Results: While effective governance is essential to promote beneficial screening practices and avoid attendant harms, screening governance organizations face enduring challenges. These challenges are social and ethical as much as technical. Evidence-based adjudication of the benefits and harms of population screening must take account of factors that inform the production and interpretation of evidence, including the divergent professional, financial and personal commitments of stakeholders. Similarly, when planning and overseeing organized screening programs, screening governance organizations must persuade or compel multiple stakeholders to work together to a common end. Screening governance organizations in different jurisdictions vary widely in how they are constituted, how they relate to other interested organizations and actors, and what powers and authority they wield. Yet we know little about how these differences affect the way screening is implemented, and with what consequences. Conclusions: Systematic research into how screening governance is organized in different jurisdictions would facilitate policy learning to address enduring challenges. Even without such research, informal exchange and sharing of experiences between screening governance organizations can deliver invaluable insights into the social as well as the technical aspects of governance