Cost-utility analysis of genetic screening in families of patients with germline MUTYH mutations

<p>Abstract</p> <p>Background</p> <p>MUTYH associated polyposis (MAP) is an autosomal recessive inherited disorder. Carriers of bi-allelic <it>MUTYH </it>germline mutations have a risk of approximately 60% to develop colorectal carcinoma (CRC). In the general population about 1.5% is a heterozygous <it>MUTYH </it>mutation carrier. Children of MAP patients have an increased risk of inheriting two <it>MUTYH </it>mutations compared to the general population, implicating an increased risk for developing CRC.</p> <p>Methods</p> <p>Using data from the literature and Dutch MAP patients (n = 40), we constructed a Markov model to perform a societal cost-utility analysis of genetic screening in MAP families. Genetic screening was done by testing the spouse first and, in case of a heterozygous spouse, also testing of the children.</p> <p>Results</p> <p>The cost of genetic screening of families of MAP patients, when compared to no genetic screening, was estimated at €25,000 per quality-adjusted life year (QALY). The presence of Fecal Occult Blood testing (FOBT) population screening only slightly increased this cost-utility ratio to €25,500 per QALY. For a MUTYH heterozygote index-patient, the ratio was €51,500 per QALY. The results of our analysis were sensitive to several of the parameters in the model, including the cost assumed for molecular genetic testing.</p> <p>Conclusion</p> <p>The costs per QALY of genetic screening in families of MAP patients are acceptable according to international standards. Therefore, genetic testing of spouses and/or children should be discussed with and offered to counselees.</p

Genomic activation of the EGFR and HER2-neu genes in a significant proportion of invasive epithelial ovarian cancers

<p>Abstract</p> <p>Background</p> <p>The status of the EGFR and HER2-neu genes has not been fully defined in ovarian cancer. An integrated analysis of both genes could help define the proportion of patients that would potentially benefit from targeted therapies.</p> <p>Methods</p> <p>We determined the tumour mutation status of the entire tyrosine kinase (TK) domain of the EGFR and HER2-neu genes in a cohort of 52 patients with invasive epithelial ovarian cancer as well as the gene copy number and protein expression of both genes in 31 of these patients by DGGE and direct sequecing, immunohistochemistry and Fluorescent in Situ Hybridisation (FISH).</p> <p>Results</p> <p>The EGFR was expressed in 59% of the cases, with a 2+/3+ staining intensity in 38%. HER2-neu expression was found in 35%, with a 2/3+ staining in 18%. No mutations were found in exons 18–24 of the TK domains of EGFR and HER2-neu. High polysomy of the EGFR gene was observed in 13% of the invasive epthelial cancers and amplification of the HER2-neu gene was found in 10% and correlated with a high expression level by immunohistochemistry.</p> <p>Mutations within the tyrosine kinase domain were not found in the entire TK domain of both genes, but have been found in very rare cases by others.</p> <p>Conclusion</p> <p>Genomic alteration of the HER2-neu and EGFR genes is frequent (25%) in ovarian cancer. EGFR/HER2-neu targeted therapies should be investigated prospectively and specifically in that subset of patients.</p

Case-finding of dementia in general practice and effects of subsequent collaborative care; design of a cluster RCT

<p>Abstract</p> <p>Background</p> <p>In the primary care setting, dementia is often diagnosed relatively late in the disease process. Case finding and proactive collaborative care may have beneficial effects on both patient and informal caregiver by clarifying the cause of cognitive decline and changed behaviour and by enabling support, care planning and access to services.</p> <p>We aim to improve the recognition and diagnosis of individuals with dementia in general practice. In addition to this diagnostic aim, the effects of case finding and subsequent care on the mental health of individuals with dementia and the mental health of their informal carers are explored.</p> <p>Methods and design</p> <p>Design: cluster randomised controlled trial with process evaluation.</p> <p>Participants: 162 individuals ≥ 65 years, in 15 primary care practices, in whom GPs suspect cognitive impairment, but without a dementia diagnosis.</p> <p>Intervention; case finding and collaborative care: 2 trained practice nurses (PNs) invite all patients with suspected cognitive impairment for a brief functional and cognitive screening. If the cognitive tests are supportive of cognitive impairment, individuals are referred to their GP for further evaluation. If dementia is diagnosed, a comprehensive geriatric assessment takes place to identify other relevant geriatric problems that need to be addressed. Furthermore, the team of GP and PN provide information and support.</p> <p>Control: GPs provide care and diagnosis as usual.</p> <p>Main study parameters: after 12 months both groups are compared on: 1) incident dementia (and MCI) diagnoses and 2) patient and caregiver quality of life (QoL-AD; EQ5D) and mental health (MH5; GHQ 12) and caregiver competence to care (SSCQ). The process evaluation concerns facilitating and impeding factors to the implementation of this intervention. These factors are assessed on the care provider level, the care recipient level and on the organisational level.</p> <p>Discussion</p> <p>This study will provide insight into the diagnostic yield and the clinical effects of case finding and collaborative care for individuals with suspected cognitive impairment, compared to usual care. A process evaluation will give insight into the feasibility of this intervention.</p> <p>The first results are expected in the course of 2013.</p> <p>Trial registration</p> <p>NTR3389</p

Cost-Effectiveness of Genotypic Antiretroviral Resistance Testing in HIV-Infected Patients with Treatment Failure

BACKGROUND: Genotypic antiretroviral resistance testing (GRT) in HIV infection with drug resistant virus is recommended to optimize antiretroviral therapy, in particular in patients with virological failure. We estimated the clinical effect, cost and cost-effectiveness of using GRT as compared to expert opinion in patients with antiretroviral treatment failure. METHODS: We developed a mathematical model of HIV disease to describe disease progression in HIV-infected patients with treatment failure and compared the incremental impact of GRT versus expert opinion to guide antiretroviral therapy. The analysis was conducted from the health care (discount rate 4%) and societal (discount rate 2%) perspective. Outcome measures included life-expectancy, quality-adjusted life-expectancy, health care costs, productivity costs and cost-effectiveness in US Dollars per quality-adjusted life-year (QALY) gained. Clinical and economic data were extracted from the large Swiss HIV Cohort Study and clinical trials. RESULTS: Patients whose treatment was optimized with GRT versus expert opinion had an increase in discounted life-expectancy and quality-adjusted life-expectancy of three and two weeks, respectively. Health care costs with and without GRT were $US 421,000 and$US 419,000, leading to an incremental cost-effectiveness ratio of $US 35,000 per QALY gained. In the analysis from the societal perspective, GRT versus expert opinion led to an increase in discounted life-expectancy and quality-adjusted life-expectancy of three and four weeks, respectively. Health care costs with and without GRT were$US 551,000 and $US 549,000, respectively. When productivity changes were included in the analysis, GRT was cost-saving. CONCLUSIONS: GRT for treatment optimization in HIV-infected patients with treatment failure is a cost-effective use of scarce health care resources and beneficial to the society at large

Dealing with Time in Health Economic Evaluation: Methodological Issues and Recommendations for Practice

Time is an important aspect of health economic evaluation, as the timing and duration of clinical events, healthcare interventions and their consequences all affect estimated costs and effects. These issues should be reflected in the design of health economic models. This article considers three important aspects of time in modelling: (1) which cohorts to simulate and how far into the future to extend the analysis; (2) the simulation of time, including the difference between discrete-time and continuous-time models, cycle lengths, and converting rates and probabilities; and (3) discounting future costs and effects to their present values. We provide a methodological overview of these issues and make recommendations to help inform both the conduct of cost-effectiveness analyses and the interpretation of their results. For choosing which cohorts to simulate and how many, we suggest analysts carefully assess potential reasons for variation in cost effectiveness between cohorts and the feasibility of subgroup-specific recommendations. For the simulation of time, we recommend using short cycles or continuous-time models to avoid biases and the need for half-cycle corrections, and provide advice on the correct conversion of transition probabilities in state transition models. Finally, for discounting, analysts should not only follow current guidance and report how discounting was conducted, especially in the case of differential discounting, but also seek to develop an understanding of its rationale. Our overall recommendations are that analysts explicitly state and justify their modelling choices regarding time and consider how alternative choices may impact on results

Congenital Diaphragmatic hernia – a review

Congenital Diaphragmatic hernia (CDH) is a condition characterized by a defect in the diaphragm leading to protrusion of abdominal contents into the thoracic cavity interfering with normal development of the lungs. The defect may range from a small aperture in the posterior muscle rim to complete absence of diaphragm. The pathophysiology of CDH is a combination of lung hypoplasia and immaturity associated with persistent pulmonary hypertension of newborn (PPHN) and cardiac dysfunction. Prenatal assessment of lung to head ratio (LHR) and position of the liver by ultrasound are used to diagnose and predict outcomes. Delivery of infants with CDH is recommended close to term gestation. Immediate management at birth includes bowel decompression, avoidance of mask ventilation and endotracheal tube placement if required. The main focus of management includes gentle ventilation, hemodynamic monitoring and treatment of pulmonary hypertension followed by surgery. Although inhaled nitric oxide is not approved by FDA for the treatment of PPHN induced by CDH, it is commonly used. Extracorporeal membrane oxygenation (ECMO) is typically considered after failure of conventional medical management for infants ≥ 34 weeks’ gestation or with weight >2 kg with CDH and no associated major lethal anomalies. Multiple factors such as prematurity, associated abnormalities, severity of PPHN, type of repair and need for ECMO can affect the survival of an infant with CDH. With advances in the management of CDH, the overall survival has improved and has been reported to be 70-90% in non-ECMO infants and up to 50% in infants who undergo ECMO

Sensitivity of South American tropical forests to an extreme climate anomaly

This is the final version. Available on open access from Nature Research via the DOI in this recordData availability: Publicly available climate data used in this paper are available from ERA5 (ref. 64), CRU ts.4.03 (ref. 65), WorldClim v2 (ref. 66), TRMM product 3B43 V7 (ref. 67) and GPCC, Version 7 (ref. 68). The input data are available on ForestPlots42.Code availability R code for graphics and analyses is available on ForestPlots42.The tropical forest carbon sink is known to be drought sensitive, but it is unclear which forests are the most vulnerable to extreme events. Forests with hotter and drier baseline conditions may be protected by prior adaptation, or more vulnerable because they operate closer to physiological limits. Here we report that forests in drier South American climates experienced the greatest impacts of the 2015–2016 El Niño, indicating greater vulnerability to extreme temperatures and drought. The long-term, ground-measured tree-by-tree responses of 123 forest plots across tropical South America show that the biomass carbon sink ceased during the event with carbon balance becoming indistinguishable from zero (−0.02 ± 0.37 Mg C ha−1 per year). However, intact tropical South American forests overall were no more sensitive to the extreme 2015–2016 El Niño than to previous less intense events, remaining a key defence against climate change as long as they are protected