Health Technology Assessment for Molecular Diagnostics: Practices, Challenges, and Recommendations from the Medical Devices and Diagnostics Special Interest Group

AbstractBackgroundHealth technology assessments (HTAs) are increasingly used to inform coverage, access, and utilization of medical technologies including molecular diagnostics (MDx). Although MDx are used to screen patients and inform disease management and treatment decisions, there is no uniform approach to their evaluation by HTA organizations.ObjectivesThe International Society for Pharmacoeconomics and Outcomes Research Devices and Diagnostics Special Interest Group reviewed diagnostic-specific HTA programs and identified elements representing common and best practices.MethodsMDx-specific HTA programs in Europe, Australia, and North America were characterized by methodology, evaluation framework, and impact. Published MDx HTAs were reviewed, and five representative case studies of test evaluations were developed: United Kingdom (National Institute for Health and Care Excellence's Diagnostics Assessment Programme, epidermal growth factor receptor tyrosine kinase mutation), United States (Palmetto's Molecular Diagnostic Services Program, OncotypeDx prostate cancer test), Germany (Institute for Quality and Efficiency in Healthcare, human papillomavirus testing), Australia (Medical Services Advisory Committee, anaplastic lymphoma kinase testing for non–small cell lung cancer), and Canada (Canadian Agency for Drugs and Technologies in Health, Rapid Response: Non-invasive Prenatal Testing).ResultsOverall, the few HTA programs that have MDx-specific methods do not provide clear parameters of acceptability related to clinical and analytic performance, clinical utility, and economic impact. The case studies highlight similarities and differences in evaluation approaches across HTAs in the performance metrics used (analytic and clinical validity, clinical utility), evidence requirements, and how value is measured. Not all HTAs are directly linked to reimbursement outcomes.ConclusionsTo improve MDx HTAs, organizations should provide greater transparency, better communication and collaboration between industry and HTA stakeholders, clearer links between HTA and funding decisions, explicit recognition of and rationale for differential approaches to laboratory-developed versus regulatory-approved test, and clear evidence requirements

Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and progressive weakness. There is considerable inter-patient variability in disease onset and progression, which can confound the results of clinical trials. Here we show that a common null polymorphism (R577X) in ACTN3 results in significantly reduced muscle strength and a longer 10\u2009m walk test time in young, ambulant patients with DMD; both of which are primary outcome measures in clinical trials. We have developed a double knockout mouse model, which also shows reduced muscle strength, but is protected from stretch-induced eccentric damage with age. This suggests that \u3b1-actinin-3 deficiency reduces muscle performance at baseline, but ameliorates the progression of dystrophic pathology. Mechanistically, we show that \u3b1-actinin-3 deficiency triggers an increase in oxidative muscle metabolism through activation of calcineurin, which likely confers the protective effect. Our studies suggest that ACTN3 R577X genotype is a modifier of clinical phenotype in DMD patients

FACETS: A cognitive business intelligence system

A cognitive decision support system called FACETS was developed and evaluated based on the situation retrieval (SR) model. The aim of FACETS is to provide decision makers cognitive decision support in ill-structured decision situations. The design and development of FACETS includes novel concepts, models, algorithms and system architecture, such as ontology and experience representation, situation awareness parsing, data warehouse query construction and guided situation presentation. The experiments showed that FACETS is able to play a significant role in supporting ill-structured decision making through developing and enriching situation awareness. © 2013 Elsevier Ltd

The emerging landscape of tumor marker panels for the identification of aggressive prostate cancer: the perspective through bibliometric analysis of an Italian translational working group in uro-oncology

Molecular heterogeneity and availability of different therapeutic strategies are relevant clinical features of prostate cancer. On this basis, there is an urgent need to identify prognostic and predictive biomarkers for an individualized therapeutic approach. In this context, researchers focused their attention on biomarkers able to discriminate potential life-threatening from organ-confined disease identify high-grade tumors. Such biomarker could provide aid in clinical decision making, helping in order to choose the treatment which ensures the best results in terms of patient survival and quality of life. To address this need, many new laboratory tests have been proposed, witha clear tendency to use panels of combined biomarkers. In this review we evaluate current data on the application in clinical practice for of the most promising laboratory tests: Phi, 4Kscore and Stockholm 3 as circulating biomarkers, and Mi-prostate score, Exo DX Prostate and Select MD-X as urinary biomarkers, Confirm MDx, Oncotype Dx, Prolaris and Decipher as tissue biomarkers. In particular, the ability of these tests in the identification of clinically significant PCa and their potential use for precision medicine have been explored in this review

What’s in a label? An exploration of how people acquire the label ‘autistic’ in adulthood and the consequences of doing so

Background. Since the 1960s the estimated prevalence of autism has increased. This has been accompanied with greater public awareness of the condition and a growing demand for diagnosis, particularly in adulthood. For sociologists, diagnoses such as autism play a fundamental role in modern social life. As well as organising the clinical picture for patients – determining their prognosis and treatment options – diagnoses also have the capacity to change how a person thinks about themselves and other people. Previous research has shown that obtaining an autism diagnosis in adulthood comes with significant benefits (greater self-awareness and access to support services) as well as some undesirable drawbacks (shame and a sense of helplessness). Yet a medical diagnosis is not the only way of acquiring the label. An individual can also label themselves – that is, self-identify – as autistic, and they can be labelled as such by other autistic people. To date, little has been done to investigate these other ways of acquiring the label, and more broadly the implications of being labelled autistic, by any means, have yet to be clearly theorised by sociologists. I aim to address these gaps in this study. Methods. I conducted a qualitative study in order to answer the question: “How do people come to be labelled, or to label themselves, as autistic in adulthood, and what are the consequences of doing so?” Using snowball and theoretical sampling, I recruited twenty-one autistic adults, eleven with a medical diagnosis and ten who self- identified as such, to take part in two loosely structured qualitative interviews (forty-two interviews in total). These accounts were analysed using a method called situational analysis, a form of constructivist grounded theory. Findings. I present three theoretical concepts that illustrate how people go about acquiring the label autistic and what it means to live with it. The first is the concept of the ‘sticky-slippy’ label, which is a figurative expression used to illustrate some of the properties of the label autistic. Once acquired, the label has an inherent ‘stickiness’ to it (a sense of permanence) whilst at the same time exhibiting more ‘slippery’ qualities (a fluid and shifting prominence in a person’s identity). The second concept relates specifically to people self-identifying as autistic and their reasons for doing so, which are conceptualised as four different ways: (1) somebody who self-identifies as autistic as a precursor to seeking a medical diagnosis, (2) somebody who self-identifies as autistic despite a negative diagnosis, (3) somebody who self-identifies as autistic as an alternative to a diagnosis, and (4) somebody who self-identifies as only having autistic traits. The third concept relates to the practice of autistic lay people labelling other lay people as autistic (which I call a ‘lay diagnosis’). Within this, I distinguish between ‘passively spotting’ and ‘actively seeking’ autism in others. Discussion. The ambition of this study is to provide a conceptual vocabulary for thinking about the nature of the label autistic, the different ways in which people can acquire it, and the implications of doing so. The concepts presented here may be applicable to other physical and psychiatric categories, of which autism serves as an illustrative example. The concept of the sticky-slippy label offers a means of understanding and reporting the consequences of being labelled autistic, something that is markedly absent in the current literature. The four ways of self-identification represent a sustained engagement with the growing phenomenon of people labelling themselves as autistic, which may be of interest to those researching the self-identification or self-diagnosis of other psychiatric conditions. Finally, I open the door on a potentially interesting research agenda: the act of lay people diagnosing other lay people with physical and psychological afflictions – lay diagnosis – which could sit alongside current research endeavours within the sociology of diagnosis

Clinical validation of a spectroscopic liquid biopsy for earlier detection of brain cancer

BackgroundDiagnostic delays impact the quality of life and survival of patients with brain tumors. Earlier and expeditious diagnoses in these patients are crucial to reduce the morbidities and mortalities associated with brain tumors. A simple, rapid blood test that can be administered easily in a primary care setting to efficiently identify symptomatic patients who are most likely to have a brain tumor would enable quicker referral to brain imaging for those who need it most.MethodsBlood serum samples from 603 patients were prospectively collected and analyzed. Patients either had non-specific symptoms that could be indicative of a brain tumor on presentation to the Emergency Department, or a new brain tumor diagnosis and referral to the neurosurgical unit, NHS Lothian, Scotland. Patient blood serum samples were analyzed using the Dxcover® Brain Cancer liquid biopsy. This technology utilizes infrared spectroscopy combined with a diagnostic algorithm to predict the presence of intracranial disease.ResultsOur liquid biopsy approach reported an area under the receiver operating characteristic curve of 0.8. The sensitivity-tuned model achieves a 96% sensitivity with 45% specificity (NPV 99.3%) and identified 100% of glioblastoma multiforme patients. When tuned for a higher specificity, the model yields a sensitivity of 47% with 90% specificity (PPV 28.4%).ConclusionsThis simple, non-invasive blood test facilitates the triage and radiographic diagnosis of brain tumor patients while providing reassurance to healthy patients. Minimizing time to diagnosis would facilitate the identification of brain tumor patients at an earlier stage, enabling more effective, less morbid surgical and adjuvant care