Time to diagnosis and determinants of diagnostic delays of people living with a rare disease: results of a Rare Barometer retrospective patient survey.

Timely diagnosis is one of the most serious challenges faced by people living with a rare disease (PLWRD), and this study estimates that in Europe, the average total diagnosis time (TDT) is close to 5 years. We investigated the duration of the TDT for PLWRD in Europe, the difficulties associated with their diagnosis odyssey and the main determinants of diagnosis delays for all rare diseases (RD). We conducted a survey of PLWRD and their families using Rare Barometer, the survey initiative of EURORDIS-Rare Diseases Europe. In geographical Europe, we surveyed 6507 people living with 1675 RD in 41 countries. We then performed a descriptive analysis and ordinal logistic regressions to identify the main determinants of diagnosis delays. Average TDT is 4.7 years. 56% of respondents were diagnosed more than 6 months after a first medical contact. The main determinants of diagnosis delays are symptom onset before 30 years of age, especially during childhood (OR = 3.11; 95% CI: 2.4-4.0) and adolescence (OR = 4.79; 95% CI: 3.7-6.2), being a woman (OR = 1.22; 95% CI:1.1-1.4), living in Northern Europe (OR = 2.15; 95% CI:1.8-2.6) or Western Europe (OR = 1.96; 95% CI:1.6-2.3), the number of healthcare professionals consulted (OR = 5.15; 95% CI:4.1-6.4), misdiagnosis (OR = 2.48; 95% CI:2.1-2.9), referral to a centre of expertise (OR = 1.17; 95% CI:1.0-1.3), unmet needs for psychological support (OR = 1.34; 95% CI:1.2-1.5) and financial support (OR = 1.16; 95% CI:1.0-1.3), having a genetic disease (OR = 1.33; 95% CI:1.1-1.5) and a family history of an RD (OR = 1.36; 95% CI:1.1-1.6). These determinants can inform policies and actions to improve access to diagnosis for all PLWRD.

Rapid exome sequencing as a first-tier test in neonates with suspected genetic disorder: results of a prospective multicenter clinical utility study in the Netherlands.

The introduction of rapid exome sequencing (rES) for critically ill neonates admitted to the neonatal intensive care unit has made it possible to impact clinical decision-making. Unbiased prospective studies to quantify the impact of rES over routine genetic testing are, however, scarce. We performed a clinical utility study to compare rES to conventional genetic diagnostic workup for critically ill neonates with suspected genetic disorders. In a multicenter prospective parallel cohort study involving five Dutch NICUs, we performed rES in parallel to routine genetic testing for 60 neonates with a suspected genetic disorder and monitored diagnostic yield and the time to diagnosis. To assess the economic impact of rES, healthcare resource use was collected for all neonates. rES detected more conclusive genetic diagnoses than routine genetic testing (20% vs. 10%, respectively), in a significantly shorter time to diagnosis (15 days (95% CI 10-20) vs. 59 days (95% CI 23-98, p < 0.001)). Moreover, rES reduced genetic diagnostic costs by 1.5% (€85 per neonate). CONCLUSION:  Our findings demonstrate the clinical utility of rES for critically ill neonates based on increased diagnostic yield, shorter time to diagnosis, and net healthcare savings. Our observations warrant the widespread implementation of rES as first-tier genetic test in critically ill neonates with disorders of suspected genetic origin. WHAT IS KNOWN: • Rapid exome sequencing (rES) enables diagnosing rare genetic disorders in a fast and reliable manner, but retrospective studies with neonates admitted to the neonatal intensive care unit (NICU) indicated that genetic disorders are likely underdiagnosed as rES is not routinely used. • Scenario modeling for implementation of rES for neonates with presumed genetic disorders indicated an expected increase in costs associated with genetic testing. WHAT IS NEW: • This unique prospective national clinical utility study of rES in a NICU setting shows that rES obtained more and faster diagnoses than conventional genetic tests. • Implementation of rES as replacement for all other genetic tests does not increase healthcare costs but in fact leads to a reduction in healthcare costs.

Guidance on development and operation of Young Persons' Advisory Groups.

BACKGROUND: Engaging patients and the public as collaborators in research is increasingly recognised as important as such partnerships can help improve research relevance and acceptability. Young Persons' Advisory Groups (YPAGs) provide a forum for clinical researchers and triallists to engage with children and young people on issues relevant to the design, conduct and translation of paediatric clinical trials. Until fairly recently, there was very little information available to guide the successful development and operation of YPAGs. OBJECTIVE: To develop an evidence-based tool to guide clinical researchers and triallists in the establishment and operation of a YPAG. METHODS: An online needs assessment survey was conducted using SurveyMonkey with 60 known paediatric drug researchers to identify knowledge gaps around YPAG engagement, development and operation. Semistructured interviews with founders and coordinators of five well-established existing YPAGs and a review of the literature were performed to identify best-practice processes for starting up and operating YPAG. RESULTS: The majority of 12 survey respondents (20%) from 12 different centres indicated that while they felt YPAGs could benefit their research, guidance on how to develop and operate a YPAG was needed. Most preferred a web-based guidance tool. Ten core steps in starting up and operating a YPAG were identified and developed into an online YPAG guidance tool, now freely accessible for use by paediatric clinical researchers worldwide. Plans to evaluate the impact are in place. CONCLUSIONS: This novel tool, developed with an internationally based group of public involvement leads working across paediatric clinical research areas, provides harmonised guidance for researchers seeking to develop and operate YPAGs to help improve the quality and impact of paediatric clinical research studies.

The Value of Diagnostic Information in Personalised Healthcare: A Comprehensive Concept to Facilitate Bringing This Technology into Healthcare Systems.

Health systems around the world seek to address patients' unmet health needs for a range of acute and chronic diseases. Simultaneously, governments strive to keep healthcare spending sustainable, while providing equal access to high-quality care. This has fuelled debate around what constitutes a valuable healthcare intervention in a health system and the corollary consideration of what governments are willing to pay for a certain health intervention. Until recently, the value of information in general, and the value of diagnostic information (VODI) specifically, was not part of the discussion.However, investment in diagnostic information can be a key development as information may guide more effective and efficient healthcare and help maintain an affordable health system. This paper therefore explores ways to best define, evaluate, and reward the value created from diagnostics in healthcare and how to include these value considerations in decision-making processes for diagnostics. The authors ultimately call for a holistic VODI framework that accounts for the full range of potential benefits of diagnostic testing, beyond the traditional clinical and health economic domains, and that is essential to recognise, measure, and fully leverage the benefits of diagnostics for patients, health systems, and society.

Recommendations for reporting results of diagnostic genetic testing (biochemical, cytogenetic and molecular genetic).

Genetic test results can have considerable importance for patients, their parents and more remote family members. Clinical therapy and surveillance, reproductive decisions and genetic diagnostics in family members, including prenatal diagnosis, are based on these results. The genetic test report should therefore provide a clear, concise, accurate, fully interpretative and authoritative answer to the clinical question. The need for harmonizing reporting practice of genetic tests has been recognised by the External Quality Assessment (EQA), providers and laboratories. The ESHG Genetic Services Quality Committee has produced reporting guidelines for the genetic disciplines (biochemical, cytogenetic and molecular genetic). These guidelines give assistance on report content, including the interpretation of results. Selected examples of genetic test reports for all three disciplines are provided in an annexe.

Perspectives of couples with high risk of transmitting genetic disorders.

OBJECTIVE: To investigate the preference for preimplantation genetic diagnosis (PGD) as an alternative to prenatal diagnosis (PND) in a large group of couples representing a wide array of genetic disorders. We also investigated the couple's familiarity with PGD and presented time trade-off scenarios for PGD versus PND, as PGD treatment is regularly accompanied by waiting lists. DESIGN: Questionnaire study. SETTING: Patient organizations representing genetic disorders. PATIENT(S): A total of 210 couples carrying genetic disorders. MAIN OUTCOME MEASURE(S): Preference for PGD or PND and familiarity with PGD in carrier couples. RESULT(S): Fifteen organizations representing 38 genetic disorders agreed to participate. Nine hundred eighty-three couples responded. In total 210 couples were in their reproductive years (women 18-40 years) and had a desire to conceive. Ninety couples (42%) had never heard of PGD. After they were informed, 127 couples (60%) wanted to have diagnostic testing (PND or PGD) performed. Ninety-four (74%) of these couples preferred testing with PGD. When no waiting list was used 102 couples (80%) preferred PGD. With a 2-year waiting list for PGD, 58 couples (46%) would opt for PGD. CONCLUSION(S): Many carrier couples are unaware of the existence of PGD. When informed, most couples prefer PGD more than PND. The preference for PGD decreases with longer waiting lists.

A patient and family perspective on gene therapy for rare diseases.

The authors describe the view of patients and patient organisations on gene therapy research and gene therapy regulations. In particular, the added value of partnership between scientists and patient organisations, and patient involvement in the gene therapy field, are addressed.

Clinical and angiographic results with the beStent: the Registry for Optimal beStent Evaluation (ROSE) trial.

BACKGROUND: Although safety and efficacy of the beStent (Medtronic Inc., Santa Rosa, CA, USA) have been described, the long-term angiographic and clinical outcomes have yet to be investigated. The ROSE (Registry for Optimal beStent Evaluation) trial was designed to assess the procedural safety of single 15 mm beStent implantation, and the six-month angiographic and 12-month clinical outcomes of patients treated with this novel coronary stent. METHODS: Patients with angina and a single de novo lesion in a native coronary artery of >/=2.75 mm diameter were included in this multicenter, prospective, observational trial. Clinical follow-up was obtained at one, six and 12 months. Angiography was performed before and after the stent implantation and at six months. The primary end-point included major adverse cardiac events (death, myocardial infarction and target lesion revascularization), major bleeding complications, and thrombotic occlusions at one-month follow-up. Secondary end-points were major cardiac-event-free survival at six- and 12-month follow-up and angiographic restenosis at six months. A total of 120 patients (80% male, mean age 58.6 +/- 10.6 years) with stable (48%) or unstable (44%) angina pectoris were allocated. The target vessel reference diameter pre-procedure was 2.85 +/- 0.52 mm. RESULTS: Minimal lumen diameter pre/post and at follow-up was 0.97 +/- 0.28 mm, 2.53 +/- 0.40 mm and 1.86 +/- 0.63 mm, respectively. Restenosis rate according to the >50% diameter stenosis criterion at six-month follow-up was 21.5%. At 12 months, the event-free survival rate was 75% (no deaths, two Q-wave and seven non-Q-wave infarctions, five bypass surgery interventions and 16 target lesion revascularizations), whilst 87% of the patients were free of angina pectoris. CONCLUSION: Despite the relatively high percentage of small vessels, the outcome of the ROSE trial is comparable to those observed in previous stent trials, indicating that the coronary beStent is safe and effective as a primary device for the treatment of native coronary artery lesions in patients with (un)stable angina pectoris.