Economic evaluation of cystic fibrosis screening: A Review of the literature, CHERE Working Paper 2006/6

Objectives: To critically examine the economic evidence on Cystic Fibrosis (CF) screening and to understand issues relating to the transferability of findings to the Australian context for policy decisions. Methods: A systematic literature search identified 25 economic studies with empirical results on CF published between 1990 and 2005. These articles were then assessed against international benchmarks on conducting and reporting of economic evaluations, focusing on the transferability of the evidence to the local setting. Results: Six studies described only costs, 12 were cost-effectiveness studies, 6 were cost-benefit studies and one had a combined design (cost utility, cost benefit and cost effectiveness). Most of the cost-effectiveness studies compared screening versus ?no-screening? but the screening programs under consideration differed markedly. Four considered neonatal screening, three prenatal screening, three pre-conception and carrier screening, and one considered all types of screening programs. The outcome measures also varied considerably between studies. One study included a quality adjusted life year measure. Cost?benefit measures mostly included economic savings ? evaded lifetime medical costs of avoiding CF child birth. Conclusion: The variability in study design, model inputs and reporting of economic evaluations of CF carrier screening raises issues on the applicability and transferability of such evidence to the Australian context.Cystic fibrosis, economic evaluation

Genetics, Insurance and Professional Practice: Survey of the Australasian Clinical Genetics Workforce

In Australia and New Zealand, by contrast with much of the developed world, insurance companies can use genetic test results to refuse cover or increase premiums for mutually-rated insurance products, including life, income protection and disability insurance. Genetics professionals regularly discuss insurance implications with clients and report the issue as a clinical challenge, yet no studies have examined clinical practices or opinions. This study surveyed genetic counsellors and clinical geneticists from Australia and New Zealand to (i) investigate variability in professional practice across the Australasian clinical genetic workforce relating to the insurance implications of genetic testing, and (ii) ascertain views regarding current regulation of the issue. There was considerable variability in training and clinical policies, especially around the communication of insurance implications. Almost half of participants reported receiving no training on the insurance implications of genetic testing, and almost 40% were unsure whether they could adequately advise clients. A number of deficits in professional knowledge and understanding of the issue were identified. Widespread concerns regarding regulation of this area were reported, with < 10% of Australian participants considering current Australian regulations as adequate to protect clients from genetic discrimination. The findings from this study highlight scope for greater education, consistency and professional training on the issue of genetics and insurance in Australasia, and strong agreement about the need for regulatory reform

Progress in the treatment of Friedreich ataxia

Friedreich ataxia (FRDA) is a progressive neurological disorder affecting approximately 1 in 29,000 individuals of European descent. At present, there is no approved pharmacological treatment for this condition however research into treatment of FRDA has advanced considerably over the last two decades since the genetic cause was identified. Current proposed treatment strategies include decreasing oxidative stress, increasing cellular frataxin, improving mitochondrial function as well as modulating frataxin controlled metabolic pathways. Genetic and cell based therapies also hold great promise. Finally, physical therapies are being explored as a means of maximising function in those affected by FRDA

Clinical practice guidelines on hemochromatosis: Asian Pacific Association for the Study of the Liver

Hereditary hemochromatosis is the result of pathogenic variants in multiple genes that can result in increased body iron stores with excess iron deposited in various organs, including the liver, pancreas, and heart. The two most important advances in the field over the past 30 years have been the identification of the HFE gene (and the associated p.Cys282Tyr substitution), and the discovery of the hormone hepcidin, which is inappropriately low in this condition and is the pathophysiological basis of the increased iron absorption. The identification of mutations in the HFE gene and subsequent studies have reshaped diagnostic algorithms resulting in a marked reduction in the need for liver biopsy. The discovery of hepcidin has resulted in many studies that have dramatically improved our understanding of iron metabolism with clear potential therapeutic implications. The variable clinical expression of hemochromatosis has puzzled clinicians and scientists, and our understanding of the factors that influence the phenotype has increased over recent years. Nevertheless, increased clinician and patient awareness, early diagnosis, and therapeutic phlebotomy to restore normal life expectancy are still the cornerstones of management. The classic triad of cirrhosis, diabetes, and skin pigmentation is now uncommon, and many patients are diagnosed with minimal or no symptoms

Neuropathology of childhood‐onset basal ganglia degeneration caused by mutation of VAC14

ObjectiveTo characterize the clinical features and neuropathology associated with recessive VAC14 mutations.MethodsWhole‐exome sequencing was used to identify the genetic etiology of a rapidly progressive neurological disease presenting in early childhood in two deceased siblings with distinct neuropathological features on post mortem examination.ResultsWe identified compound heterozygous variants in VAC14 in two deceased siblings with early childhood onset of severe, progressive dystonia, and neurodegeneration. Their clinical phenotype is consistent with the VAC14–related childhood‐onset, striatonigral degeneration recently described in two unrelated children. Post mortem examination demonstrated prominent vacuolation associated with degenerating neurons in the caudate nucleus, putamen, and globus pallidus, similar to previously reported ex vivo vacuoles seen in the late‐endosome/lysosome of VAC14‐deficient neurons. We identified upregulation of ubiquitinated granules within the cell cytoplasm and lysosomal‐associated membrane protein (LAMP2) around the vacuole edge to suggest a process of vacuolation of lysosomal structures associated with active autophagocytic‐associated neuronal degeneration.InterpretationOur findings reveal a distinct clinicopathological phenotype associated with recessive VAC14 mutations.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142276/1/acn3487_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142276/2/acn3487.pd

Pharmacological screening using an FXN-EGFP cellular genomic reporter assay for the therapy of Friedreich ataxia

Copyright @ 2013 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Friedreich ataxia (FRDA) is an autosomal recessive disorder characterized by neurodegeneration and cardiomyopathy. The presence of a GAA trinucleotide repeat expansion in the first intron of the FXN gene results in the inhibition of gene expression and an insufficiency of the mitochondrial protein frataxin. There is a correlation between expansion length, the amount of residual frataxin and the severity of disease. As the coding sequence is unaltered, pharmacological up-regulation of FXN expression may restore frataxin to therapeutic levels. To facilitate screening of compounds that modulate FXN expression in a physiologically relevant manner, we established a cellular genomic reporter assay consisting of a stable human cell line containing an FXN-EGFP fusion construct, in which the EGFP gene is fused in-frame with the entire normal human FXN gene present on a BAC clone. The cell line was used to establish a fluorometric cellular assay for use in high throughput screening (HTS) procedures. A small chemical library containing FDA-approved compounds and natural extracts was screened and analyzed. Compound hits identified by HTS were further evaluated by flow cytometry in the cellular genomic reporter assay. The effects on FXN mRNA and frataxin protein levels were measured in lymphoblast and fibroblast cell lines derived from individuals with FRDA and in a humanized GAA repeat expansion mouse model of FRDA. Compounds that were established to increase FXN gene expression and frataxin levels included several anti-cancer agents, the iron-chelator deferiprone and the phytoalexin resveratrol.Muscular Dystrophy Association (USA), the National Health and Medical Research Council (Australia), the Friedreich’s Ataxia Research Alliance (USA), the Brockhoff Foundation (Australia), the Friedreich Ataxia Research Association (Australasia), Seek A Miracle (USA) and the Victorian Government’s Operational Infrastructure Support Program

Utility and limitations of hepascore and transient elastography to detect advanced hepatic fibrosis in HFE hemochromatosis

Aspartate aminotransferase-to-platelet ratio index (APRI) and Fibrosis-4 Index (Fib4) have been validated against liver biopsy for detecting advanced hepatic fibrosis in HFE hemochromatosis. We determined the diagnostic utility for advanced hepatic fibrosis of Hepascore and transient elastography compared with APRI and Fib4 in 134 newly diagnosed HFE hemochromatosis subjects with serum ferritin levels \u3e 300 µg/L using area under the receiver operator characteristic curve (AUROC) analysis and APRI- ( \u3e 0.44) or Fib4- ( \u3e 1.1) cut-offs for AHF, or a combination of both. Compared with APRI, Hepascore demonstrated an AUROC for advanced fibrosis of 0.69 (95% CI 0.56–0.83; sensitivity = 69%, specificity = 65%; P = 0.01) at a cut-off of 0.22. Using a combination of APRI and Fib4, the AUROC for Hepascore for advanced fibrosis was 0.70 (95% CI 0.54–0.86, P = 0.02). Hepascore was not diagnostic for detection of advanced fibrosis using the Fib4 cut-off. Elastography was not diagnostic using either APRI or Fib4 cut-offs. Hepascore and elastography detected significantly fewer true positive or true negative cases of advanced fibrosis compared with APRI and Fib4, except in subjects with serum ferritin levels \u3e 1000 µg/L. In comparison with APRI or Fib4, Hepascore or elastography may underdiagnose advanced fibrosis in HFE Hemochromatosis, except in individuals with serum ferritin levels \u3e 1000 µg/L

Efficacy of Omaveloxolone in Friedreich's Ataxia: Delayed-Start Analysis of the MOXIe Extension

BACKGROUND: MOXIe was a two-part study evaluating the safety and efficacy of omaveloxolone in patients with Friedreich's ataxia, a rare, progressive neurological disease with no proven therapy. MOXIe part 2, a randomized double-blind placebo-controlled trial, showed omaveloxolone significantly improved modified Friedreich's Ataxia Rating Scale (mFARS) scores relative to placebo. Patients who completed part 1 or 2 were eligible to receive omaveloxolone in an open-label extension study. OBJECTIVE: The delayed-start study compared mFARS scores at the end of MOXIe part 2 with those at 72 weeks in the open-label extension period (up to 144 weeks) for patients initially randomized to omaveloxolone versus those initially randomized to placebo. METHODS: We performed a noninferiority test to compare the difference between treatment groups (placebo to omaveloxolone versus omaveloxolone to omaveloxolone) using a single mixed model repeated measures (MMRM) model. In addition, slopes of the change in mFARS scores were compared between both groups in the open-label extension. RESULTS: The noninferiority testing demonstrated that the difference in mFARS between omaveloxolone and placebo observed at the end of placebo-controlled MOXIe part 2 (-2.17 ± 1.09 points) was preserved after 72 weeks in the extension (-2.91 ± 1.44 points). In addition, patients previously randomized to omaveloxolone in MOXIe part 2 continued to show no worsening in mFARS relative to their extension baseline through 144 weeks. CONCLUSIONS: These results support the positive results of MOXIe part 2 and indicate a persistent benefit of omaveloxolone treatment on disease course in Friedreich's ataxia. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Propensity matched comparison of omaveloxolone treatment to Friedreich ataxia natural history data

OBJECTIVE: The natural history of Friedreich ataxia is being investigated in a multi-center longitudinal study designated the Friedreich ataxia Clinical Outcome Measures Study (FACOMS). To understand the utility of this study in analysis of clinical trials, we performed a propensity-matched comparison of data from the open-label MOXIe extension (omaveloxolone) to that from FACOMS. METHODS: MOXIe extension patients were matched to FACOMS patients using logistic regression to estimate propensity scores based on multiple covariates: sex, baseline age, age of onset, baseline modified Friedreich Ataxia Rating scale (mFARS) score, and baseline gait score. The change from baseline in mFARS at Year 3 for the MOXIe extension patients compared to the matched FACOMS patients was analyzed as the primary efficacy endpoint using mixed model repeated measures analysis. RESULTS: Data from the MOXIe extension show that omaveloxolone provided persistent benefit over 3 years when compared to an untreated, matched cohort from FACOMS. At each year, in all analysis populations, patients in the MOXIe extension experienced a smaller change from baseline in mFARS score than matched FACOMS patients. In the primary pooled population (136 patients in each group) by Year 3, patients in the FACOMS matched set progressed 6.6 points whereas patients treated with omaveloxolone in MOXIe extension progressed 3 points (difference = -3.6; nominal p value = 0.0001). INTERPRETATION: These results suggest a meaningful slowing of Friedreich ataxia progression with omaveloxolone, and consequently detail how propensity-matched analysis may contribute to understanding of effects of therapeutic agents. This demonstrates the direct value of natural history studies in clinical trial evaluations

Clinical management guidelines for Friedreich ataxia : best practice in rare diseases

BACKGROUND: Individuals with Friedreich ataxia (FRDA) can find it difficult to access specialized clinical care. To facilitate best practice in delivering healthcare for FRDA, clinical management guidelines (CMGs) were developed in 2014. However, the lack of high-certainty evidence and the inadequacy of accepted metrics to measure health status continues to present challenges in FRDA and other rare diseases. To overcome these challenges, the Grading of Recommendations Assessment and Evaluation (GRADE) framework for rare diseases developed by the RARE-Bestpractices Working Group was adopted to update the clinical guidelines for FRDA. This approach incorporates additional strategies to the GRADE framework to support the strength of recommendations, such as review of literature in similar conditions, the systematic collection of expert opinion and patient perceptions, and use of natural history data. METHODS: A panel representing international clinical experts, stakeholders and consumer groups provided oversight to guideline development within the GRADE framework. Invited expert authors generated the Patient, Intervention, Comparison, Outcome (PICO) questions to guide the literature search (2014 to June 2020). Evidence profiles in tandem with feedback from individuals living with FRDA, natural history registry data and expert clinical observations contributed to the final recommendations. Authors also developed best practice statements for clinical care points that were considered self-evident or were not amenable to the GRADE process. RESULTS: Seventy clinical experts contributed to fifteen topic-specific chapters with clinical recommendations and/or best practice statements. New topics since 2014 include emergency medicine, digital and assistive technologies and a stand-alone section on mental health. Evidence was evaluated according to GRADE criteria and 130 new recommendations and 95 best practice statements were generated. DISCUSSION AND CONCLUSION: Evidence-based CMGs are required to ensure the best clinical care for people with FRDA. Adopting the GRADE rare-disease framework enabled the development of higher quality CMGs for FRDA and allows individual topics to be updated as new evidence emerges. While the primary goal of these guidelines is better outcomes for people living with FRDA, the process of developing the guidelines may also help inform the development of clinical guidelines in other rare diseases