Qualitative research within trials: developing a standard operating procedure for a clinical trials unit

<p>BACKGROUND: Qualitative research methods are increasingly used within clinical trials to address broader research questions than can be addressed by quantitative methods alone. These methods enable health professionals, service users, and other stakeholders to contribute their views and experiences to evaluation of healthcare treatments, interventions, or policies, and influence the design of trials. Qualitative data often contribute information that is better able to reform policy or influence design.</p> <p>METHODS: Health services researchers, including trialists, clinicians, and qualitative researchers, worked collaboratively to develop a comprehensive portfolio of standard operating procedures (SOPs) for the West Wales Organisation for Rigorous Trials in Health (WWORTH), a clinical trials unit (CTU) at Swansea University, which has recently achieved registration with the UK Clinical Research Collaboration (UKCRC). Although the UKCRC requires a total of 25 SOPs from registered CTUs, WWORTH chose to add an additional qualitative-methods SOP (QM-SOP).</p> <p>RESULTS: The qualitative methods SOP (QM-SOP) defines good practice in designing and implementing qualitative components of trials, while allowing flexibility of approach and method. Its basic principles are that: qualitative researchers should be contributors from the start of trials with qualitative potential; the qualitative component should have clear aims; and the main study publication should report on the qualitative component.</p> <p>CONCLUSIONS: We recommend that CTUs consider developing a QM-SOP to enhance the conduct of quantitative trials by adding qualitative data and analysis. We judge that this improves the value of quantitative trials, and contributes to the future development of multi-method trials.</p&gt

NGS Analysis for Molecular Diagnosis of Retinitis Pigmentosa (RP): Detection of a Novel Variant in PRPH2 Gene

This work describes the application of NGS for molecular diagnosis of RP in a family with a history of severe hypovision. In particular, the proband received a clinical diagnosis of RP on the basis of medical, instrumental examinations and his family history. The proband was subjected to NGS, utilizing a customized panel including 24 genes associated with RP and other retinal dystrophies. The NGS analysis revealed a novel missense variant (c.668T > A, I223N) in PRPH2 gene, which was investigated by segregation and bioinformatic analysis. The variant is located in the D2 loop domain of PRPH2, which is critical for protein activity. Bioinformatic analysis described the c.668T > A as a likely pathogenic variant. Moreover, a 3D model prediction was performed to better characterize the impact of the variant on the protein, reporting a disruption of the \u3b1-helical structures. As a result, the variant protein showed a substantially different conformation with respect to the wild-type PRPH2. The identified variant may therefore affect the oligomerization ability of the D2 loop and, ultimately, hamper PRPH2 proper functioning and localization. In conclusion, PRPH2_c.668T > A provided a molecular explanation of RP symptomatology, highlighting the clinical utility of NGS panels to facilitate genotype\u2013phenotype correlations

Limb-Girdle Muscular Dystrophies (LGMDs): The Clinical Application of NGS Analysis, a Family Case Report

The diagnosis of LGMD2A (calpainopathy) can be challenging due to genetic heterogeneity and to high similarity with other LGMDs or neuromuscular disorders. In this setting, NGS panels are highly recommended to perform differential diagnosis, identify new causative mutations and enable genotype-phenotype correlations. In this manuscript, the case of a patient affected by LGMD2A is reported, for which the application of a defined custom designed NGS panel allowed to confirm the diagnosis of calpainopathy linked with two heterozygous variants in CAPN3, namely c.550delA and c.1813G>C. The first variant has been extensively described in relation to calpainopathy. The second variant c.1813G>C, instead, is novel and has been predicted to be probably damaging. In addition, NGS analysis on the proband revealed a heterozygous variant (c.550C>T) in the LMNA gene, which is associated with dilated cardiomyopathy. The variant is novel and has been predicted to be deleterious by subsequent bioinformatic analysis. Successively, segregation analysis was performed on family members. Interestingly, none of them showed neuromuscular symptoms but the mother was diagnosed with bradycardia and syncopal episodes and showed a positive family history for cardiomyopathy. The segregation analysis reported that the proband inherited the c.1813G>C (CAPN3) from the father who was a healthy carrier. The mother was positive for c.550delA (CAPN3) and c.550C>T (LMNA), suggesting thereby a possible genetic explanation for her cardiovascular problems. Segregation analysis, therefore, confirmed the inheritance pattern of the variants carried by the proband and highlighted a familiarity for cardiomyopathy which should not be neglected. The NGS analysis was further performed on the partner of the proband, to estimate the reproductive risk of the couple. The partner was negative to NGS screening, suggesting thereby a low risk to have an affected child with calpainopathy and 50% probability inherit the LMNA variant. This case report showed the clinical utility of the NGS panel in providing accurate LGMD2A diagnosis and identifying complex phenotypes originating from mutations in multiple genes. However, NGS results should always be accomplished by a dedicated genetic counseling, not only to evaluate the recurrence and reproductive risks but also to uncover unexpected findings which can be clinically significant

Support and Assessment for Fall Emergency Referrals (SAFER) 2: a cluster randomised trial and systematic review of clinical effectiveness and cost-effectiveness of new protocols for emergency ambulance paramedics to assess older people following a fall with referral to community-based care when appropriate.

BACKGROUND: Emergency calls are frequently made to ambulance services for older people who have fallen, but ambulance crews often leave patients at the scene without any ongoing care. We evaluated a new clinical protocol which allowed paramedics to assess older people who had fallen and, if appropriate, refer them to community-based falls services. OBJECTIVES: To compare outcomes, processes and costs of care between intervention and control groups; and to understand factors which facilitate or hinder use. DESIGN: Cluster randomised controlled trial. PARTICIPANTS: Participating paramedics at three ambulance services in England and Wales were based at stations randomised to intervention or control arms. Participants were aged 65 years and over, attended by a study paramedic for a fall-related emergency service call, and resident in the trial catchment areas. INTERVENTIONS: Intervention paramedics received a clinical protocol with referral pathway, training and support to change practice. Control paramedics continued practice as normal. OUTCOMES: The primary outcome comprised subsequent emergency health-care contacts (emergency admissions, emergency department attendances, emergency service calls) or death at 1 month and 6 months. Secondary outcomes included pathway of care, ambulance service operational indicators, self-reported outcomes and costs of care. Those assessing outcomes remained blinded to group allocation. RESULTS: Across sites, 3073 eligible patients attended by 105 paramedics from 14 ambulance stations were randomly allocated to the intervention group, and 2841 eligible patients attended by 110 paramedics from 11 stations were randomly allocated to the control group. After excluding dissenting and unmatched patients, 2391 intervention group patients and 2264 control group patients were included in primary outcome analyses. We did not find an effect on our overall primary outcome at 1 month or 6 months. However, further emergency service calls were reduced at both 1 month and 6 months; a smaller proportion of patients had made further emergency service calls at 1 month (18.5% vs. 21.8%) and the rate per patient-day at risk at 6 months was lower in the intervention group (0.013 vs. 0.017). Rate of conveyance to emergency department at index incident was similar between groups. Eight per cent of trial eligible patients in the intervention arm were referred to falls services by attending paramedics, compared with 1% in the control arm. The proportion of patients left at scene without further care was lower in the intervention group than in the control group (22.6% vs. 30.3%). We found no differences in duration of episode of care or job cycle. No adverse events were reported. Mean cost of the intervention was £17.30 per patient. There were no significant differences in mean resource utilisation, utilities at 1 month or 6 months or quality-adjusted life-years. In total, 58 patients, 25 paramedics and 31 stakeholders participated in focus groups or interviews. Patients were very satisfied with assessments carried out by paramedics. Paramedics reported that the intervention had increased their confidence to leave patients at home, but barriers to referral included patients' social situations and autonomy. CONCLUSIONS: Findings indicate that this new pathway may be introduced by ambulance services at modest cost, without risk of harm and with some reductions in further emergency calls. However, we did not find evidence of improved health outcomes or reductions in overall NHS emergency workload. Further research is necessary to understand issues in implementation, the costs and benefits of e-trials and the performance of the modified Falls Efficacy Scale. TRIAL REGISTRATION: Current Controlled Trials ISRCTN60481756 and PROSPERO CRD42013006418. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 13. See the NIHR Journals Library website for further project information

Involving older people in a multi-centre randomised trial of a complex intervention in pre-hospital emergency care: implementation of a collaborative model

Background Health services research is expected to involve service users as active partners in the research process, but few examples report how this has been achieved in practice in trials. We implemented a model to involve service users in a multi-centre randomised controlled trial in pre-hospital emergency care. We used the generic Standard Operating Procedure (SOP) from our Clinical Trials Unit (CTU) as the basis for creating a model to fit the context and population of the SAFER 2 trial. Methods In our model, we planned to involve service users at all stages in the trial through decision-making forums at 3 levels: 1) strategic; 2) site (e.g. Wales; London; East Midlands); 3) local. We linked with charities and community groups to recruit people with experience of our study population. We collected notes of meetings alongside other documentary evidence such as attendance records and study documentation to track how we implemented our model. Results We involved service users at strategic, site and local level. We also added additional strategic level forums (Task and Finish Groups and Writing Days) where we included service users. Service user involvement varied in frequency and type across meetings, research stages and locations but stabilised and increased as the trial progressed. Conclusion Involving service users in the SAFER 2 trial showed how it is feasible and achievable for patients, carers and potential patients sharing the demographic characteristics of our study population to collaborate in a multi-centre trial at the level which suited their health, location, skills and expertise. A standard model of involvement can be tailored by adopting a flexible approach to take account of the context and complexities of a multi-site trial

A multiplex molecular assay for the detection of uniparental disomy for human chromosome 15

Uniparental disomy (UPD) describes the inheritance of both homologues of a pair of chromosomes from only one parent. During the last two decades, the clinical impact of UPD and associated imprinting disorders, such as Prader-Willi syndrome (PWS) and Angelman syndrome (AS) increasingly have come to our attention. About 25% of PWS and 3%-5% of AS are a consequence of UPD with the resulting phenotype generated from the parent of origin of the disomic pair of chromosomes 15. Chromosome 15 UPD testing is relevant in various prenatal diagnostic conditions including apparent confined placental mosaicism, homologous and nonhomologous Robertsonian translocations involving chromosome 15 and 14, and as genomic biomarker for detecting chromosome origin. In this work we developed and validated a two fluorescent STRs multiplex assay for a rapid, economic and fully informative detection of UPD 15 by capillary electrophoresis

PSORS2 markers are not associated with psoriatic arthritis in the Italian population

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy characterized by the association of arthritis and psoriasis (Ps). The precise etiology of PsA is unknown, but epidemiological studies supported the existence of a genetic component for the disease. Here we report an association study on a large PsA Italian cohort for DNA variants recently reported as associated alleles at PSORS2 (17q25) in Ps cohorts from the US. We focused on discovering a possible involvement of PSORS2 associated SNPs in pathogenesis of PsA. We selected two SNPs (rs7420, rs734232) within the proximal peak and two SNPs (rs869190 and rs1561946) within distal peak of PSORS2. Our results ruled out PSORS2 alleles as susceptibility factors in arthritis psoriatic patients of Italian origin and suggested that previous linkage signal reported for chromosome 17q25 should be independent on the presence of PsA