Polygenetische risicopredictie van veelvoorkomende ziekten: Van epidemiologie naar klinische toepassing

Sinds in 2001 de eerste kaart van het volledige genoom werd gepubliceerd, is de kennis over onze genetische code exponentieel toegenomen. Naast hoogrisicogenen voor monogenetische ziekten, zoals de ziekte van Huntington en cystische fibrose, zijn er voor veelvoorkomende ziekten als borstkanker en hart- en vaatziekten middels genoombrede associatiestudies vele genetische varianten geïdentificeerd die elk een klein risicoverhogend effect hebben. Op basis van deze ‘single nucleotide polymorphisms’ (SNP’s) kan een polygenetische risicoscore (PRS) worden berekend, waarmee steeds accurater een inschatting van het individuele ziekterisico kan worden gemaakt. De resultaten van epidemiologische studies waarin een PRS wordt gebruikt om iemands totale genetische risico op bepaalde ziekten te voorspellen, zijn veelbelovend. In de toekomst is de PRS mogelijk een waardevolle aanvulling op traditionele monogenetische tests, maar het is van belang dat de voorspellende waarde van de genetische risicoprofielen verder toeneemt en dat duidelijker wordt hoe de clinicus zo’n genetisch risicoprofiel – in combinatie met traditionele risicofactoren – moet interpreteren

F18-fluorodeoxyglucose single-photon emission computed tomography predicts fuctional outcome of dyssynergic myocardium after surgical revascularization

Background. Prediction of functional recovery after revascularization is possible with positron emission tomography and F18-fluorodeoxyglucose (FDG). Recently, the use of FDG in combination with single-photon emission computed tomography (SPECT), with 511 keV collimators, has been proposed to allow more widespread use of FDG. In the current study we aimed to predict improvement of regional left ventricular function after surgical revascularization with FDG and SPECT. Methods and Results. Twenty-seven patients with regional wall motion abnormalities (on echocardiography) underwent early thallium-201 (Tl-201) SPECT to assess perfusion and FDG SPECT to assess regional glucose uptake. The left ventricular myocardium was divided into 13 segments. For each segment, tracer uptake was evaluated visually (with the use of a 4-point scoring system) by consensus of two observers. Myocardial viability was determined in dyssynergic segments on echocardiography and defined as normal perfusion or increased FDG uptake in a perfusion defect (mismatch). Absence of viability was defined as a perfusion defect without increased FDG uptake (match). Improvement of regional wall motion was assessed 3 months after revascularization. In the group of segments that were viable on FDG/Tl-201 SPECT (n = 64), the segmental wall motion score decreased from 1.4 ± 0.5 to 0.6 ± 0.7 (p < 0.01), whereas the segmental wall motion score remained unchanged in nonviable segments (n = 72): 1.6 ± 0.5 versus 1.5 ± 0.6 (not significant). Forty-six (72%) of the 64 segments that were viable on FDG/Tl-201 SPECT demonstrated improved contractile function after coronary revascularization. In contrast, only 7 (10%) of 72 nonviable segments on FDG/Tl-201 SPECT showed improvement in function after revascularization (p < 0.01 versus viable segments). The sensitivity, specificity, and positive and negative predictive values were 87%, 78%, 72%, and 90%, respectively. Conclusion. This study shows that FDG/Tl-201 SPECT can identify patients who improve in regional ventricular function after revascularization

Short-term effect of low-dose colchicine on inflammatory biomarkers, lipids, blood count and renal function in chronic coronary artery disease and elevated high-sensitivity C-reactive protein

Contains fulltext : 223833.pdf (publisher's version ) (Open Access

Aggregated N-of-1 trials for unlicensed medicines for small populations: an assessment of a trial with ephedrine for myasthenia gravis

Background: Inexpensive medicines with a long history of use may currently be prescribed off-label for rare indications. Reimbursement is at the discretion of health insurance companies, and may be unpredictable. The example addressed was ephedrine as add-on treatment for myasthenia gravis. Stakeholders from academia, a patient organization, the Dutch National Health Care Institute (NHCI) and Dutch Medicines Evaluation Board (MEB) advised on the trial design. The NHCI and MEB agreed to provide scientific advice on the suitability of the evidence generated by the trial, for regulatory decisions. This paper describes the feasibility of the trial and the utility of its aggregated results. Results: The trialists experienced the trial as feasible. Retrospective interviews showed that the trial as performed was acceptable to patients. The treatment effect in the primary outcome measure, muscle strength, was statistically significant when inferred to the population level, though the effect size was modest. Secondary outcomes were statistically significant in a preplanned, fixed effects analysis within the four patients. The NHCI advised that it could potentially make reimbursement decisions based on the Fitting Evidence framework, should the trialists decide to apply for reimbursement. The MEB advised that for a licensing decision, the N-of-1 design is a last-resort option for demonstrating treatment benefit in a rare disease. N-of-1 trials alone do not provide enough evidence on potential risk. The MEB found the current trial inconclusive. It suggested doing a 2-armed trial of longer duration, possibly with a different outcome measure (postponement of corticosteroid use). It suggested engaging a consultancy or commercial sponsor, should the trialists decide to seek market authorization of the drug. Conclusions: In theory, evidence from aggregated N-of-1 trials is suitable for use in licensing and reimbursement decisions. The current example illustrates differences in interpretation of N-of-1 results by health authorities. In the era of personalized medicine, consensus is required on the interpretation of data from study designs geared to small groups. Demonstrating effectiveness of inexpensive medicines in small populations may require involvement of non-commercial parties, to preserve affordability

How to integrate personalized medicine into prevention? recommendations from the personalized prevention of chronic diseases (precedi) consortium

Medical practitioners are increasingly adopting a personalized medicine (PM) approach involving individually tailored patient care. The Personalized Prevention of Chronic Diseases (PRECeDI) consortium project, funded within the Marie Sk\u142odowska Curie Action (MSCA) Research and Innovation Staff Exchange (RISE) scheme, had fostered collaboration on PM research and training with special emphasis on the prevention of chronic diseases. From 2014 to 2018, the PRECeDI consortium trained 50 staff members on personalized prevention of chronic diseases through training and research. The acquisition of skills from researchers came from dedicated secondments from academic and nonacademic institutions aimed at training on several research topics related to personalized prevention of cancer and cardiovascular and neurodegenerative diseases. In detail, 5 research domains were addressed: (1) identification and validation of biomarkers for the primary prevention of cardiovascular diseases, secondary prevention of Alzheimer disease, and tertiary prevention of head and neck cancer; (2) economic evaluation of genomic applications; (3) ethical-legal and policy issues surrounding PM; (4) sociotechnical analysis of the pros and cons of informing healthy individuals on their genome; and (5) identification of organizational models for the provision of predictive genetic testing. Based on the results of the research carried out by the PRECeDI consortium, in November 2018, a set of recommendations for policy makers, scientists, and industry has been issued, with the main goal to foster the integration of PM approaches in the field of chronic disease prevention