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Background: Stool DNA testing for early detection of colorectal cancer (CRC) is a non-invasive technology with the potential to supplement established CRC screening tests. The aim of this health technology assessment was to evaluate effectiveness and safety of currently CE-marked stool DNA tests, compared to other CRC tests in CRC screening strategies in an asymptomatic screening population.Methods: The assessment was carried out following the guidelines of the European Network for Health Technology Assessment (EUnetHTA). This included a systematic literature search in MED-LINE, Cochrane and EMBASE in 2018. Manufacturers were asked to provide additional data. Five patient interviews helped assessing potential ethical or social aspects and patients’ experiences and preferences. We assessed the risk of bias using QUADAS-2, and the quality of the body of evidence using GRADE.Results: We identified three test accuracy studies, two of which investigated a multitarget stool DNA test (Cologuard, compared fecal immunochemical test (FIT)) and one a combined DNA stool assay (ColoAlert, compared to guaiac-based fecal occult blood test (gFOBT), Pyruvate Kinase Isoenzyme Type M2 (M2-PK) and combined gFOBT/M2-PK). We found five published surveys on patient satisfaction. No primary study investigating screening effects on CRC incidence or on overall mortality was found. Both stool DNA tests showed in direct comparison higher sensitivity for the detection of CRC and (advanced) adenoma compared to FIT, or gFOBT, respectively, but had lower specificity. However, these comparative results may depend on the exact type of FIT used. The reported test failure rates were higher for stool DNA testing than for FIT. The certainty of evidence was moderate to high for Cologuard studies, and low to very low for the ColoAlert study which refers to a former version of the product and yielded no direct evidence on the test accuracy for ad-vanced versus non-advanced adenoma.Conclusions: ColoAlert is the only stool DNA test currently sold in Europe and is available at a lower price than Cologuard, but reliable evidence is lacking. A screening study including the current product version of ColoAlert and suitable comparators would, therefore, help evaluate the effectiveness of this screening option in a European context.

Background: Damage to the central nervous system can occur in adulthood, for example, due to stroke, trauma, tumours, or chronic diseases. After damage to the central nervous system, cognitive impairments occur in addition to physical limitations. Occupational therapy is most often prescribed for neurological diagnoses, including stroke and traumatic brain injury. Methods: The health technology assessment (HTA) report this HTA article is based on investigates the clinical effectiveness, cost-effectiveness, and patient-related, social and ethical aspects of occupational therapy for patients with cognitive impairments compared to no occupational therapy. In addition, the effects of different occupational therapy interventions with and without cognitive components were compared in an explorative overview. Patients with moderate or severe dementia are excluded from the assessment. Systematic overviews, that is, systematic reviews of systematic reviews, were conducted.Results: For the evaluation of clinical effectiveness, a total of nine systematic reviews were included. No systematic review was identified for the assessment of costs or cost-effectiveness. Five systematic reviews were included for the assessment of patient and social aspects.For the assessment of clinical effectiveness compared with no occupational therapy, five systematic reviews comprising 20 randomised controlled trials with a total of 1,316 subjects reported small positive effects for the outcomes “global cognitive function” and “activities of daily living” as well as a non-quantified positive effect on the outcomes “health-related quality of life” and “behavioural control”. No effect was found for individual components of cognition and measures of perception. The quality of the evidence for all outcomes is low due to a high risk of bias.In the supplementary presentations, no positive effects could be demonstrated on the basis of the available evidence. The quality of this evidence was not assessed.For the assessment of patient and social aspects, five systematic reviews on patients with a stroke or a traumatic brain injury – without specification regarding cognitive deficits or studies with their relatives – were included.It was reported that patients and family caregivers go through different phases of rehabilitation in which the discharge home is a decisive turning point. The discharge home represents a crucial breaking point. Regaining an active, self-determining role is a process that requires therapists to find the right level of support for patients and relatives.For the assessment of ethical aspects, nine documents were included. We identified ethical problem-solving models for occupational therapy and 16 ethical aspects in occupational therapy for cognitive deficits. The central theme of the analysis is the limited autonomy due to the consequences of the disease as well as the resulting tensions with those treating the patient.Conclusions: Based on this systematic overview, it can neither be proven nor excluded with certainty that occupational therapy for cognitive impairment is an effective therapy for adult patients with central nervous system injuries compared to no occupational therapy. There is a lack of randomised trials with sufficient sample size, well-defined interventions, and comparable concomitant therapies in the control groups, but there is also a lack of well-designed observational studies in routine care and health economic studies.The identified systematic reviews on patient and social aspects provide information on the needs of patients after stroke or traumatic brain injury and their relatives, but there is a lack of studies on this aspect in German-speaking countries.For the ethical assessment, in addition to the identified theoretical models for solving ethical conflicts in occupational therapy, more empirical studies on ethical aspects with patients with cognitive deficits and their relatives as well as occupational therapists are needed.

Objective: The goal of this review was to identify decision-analytic modeling studies in early health technology assessments (HTA) of high-risk medical devices, published over the last three years, and to provide a systematic overview of model purposes and characteristics. Additionally, the aim was to describe recent developments in modeling techniques.Methods: For this scoping review, we performed a systematic literature search in PubMed and Embase including studies published in English or German. The search code consisted of terms describing early health technology assessment and terms for decision-analytic models. In abstract and full-text screening, studies were excluded that were not modeling studies for a high-risk medical device or an in-vitro diagnostic test. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram was used to report on the search and exclusion of studies. For all included studies, study purpose, framework and model characteristics were extracted and reported in systematic evidence tables and a narrative summary.Results: Out of 206 identified studies, 19 studies were included in the review. Studies were either conducted for hypothetical devices or for existing devices after they were already available on the market. No study extrapolated technical data from early development stages to estimate potential value of devices in development. All studies except one included cost as an outcome. Two studies were budget impact analyses. Most studies aimed at adoption and reimbursement decisions. The majority of studies were on in-vitro diagnostic tests for personalized and targeted medicine. A timed automata model, to our knowledge a model type new to HTA, was tested by one study. It describes the agents in a clinical pathway in separate models and, by allowing for interaction between the models, can reflect complex individual clinical pathways and dynamic system interactions. Not all sources of uncertainty for in-vitro tests were explicitly modeled. Elicitation of expert knowledge and judgement was used for substitution of missing empirical data. Analysis of uncertainty was the most valuable strength of decision-analytic models in early HTA, but no model applied sensitivity analysis to optimize the test positivity cutoff with regard to the benefit-harm balance or cost-effectiveness. Value-of-information analysis was rarely performed. No information was found on the use of causal inference methods for estimation of effect parameters from observational data.Conclusion: Our review provides an overview of the purposes and model characteristics of nineteen recent early evaluation studies on medical devices. The review shows the growing importance of personalized interventions and confirms previously published recommendations for careful modeling of uncertainties surrounding diagnostic devices and for increased use of value-of-information analysis. Timed automata may be a model type worth exploring further in HTA. In addition, we recommend to extend the application of sensitivity analysis to optimize positivity criteria for in-vitro tests with regard to benefit-harm or cost-effectiveness. We emphasize the importance of causal inference methods when estimating effect parameters from observational data.

Objectives: Public health decision making is a complex process based on thorough and comprehensive health technology assessments involving the comparison of different strategies, values and tradeoffs under uncertainty. This process must be based on best available evidence and plausible assumptions. Causal inference and health decision science are two methodological approaches providing information to help guide decision making in health care. Both approaches are quantitative methods that use statistical and modeling techniques and simplifying assumptions to mimic the complexity of the real world. We intend to review and lay out both disciplines with their aims, strengths and limitations based on a combination of textbook knowledge and expert experience.Methods: To help understanding and differentiating the methodological approaches of causal inference and health decision science, we reviewed both methods with the focus on aims, research questions, methods, assumptions, limitations and challenges, and software. For each methodological approach, we established a group of four experts from our own working group to carefully review and summarize each method, followed by structured discussion rounds and written reviews, in which the experts from all disciplines including HTA and medicine were involved. The entire expert group discussed objectives, strengths and limitations of both methodological areas, and potential synergies. Finally, we derived recommendations for further research and provide a brief outlook on future trends.Results: Causal inference methods aim for drawing causal conclusions from empirical data on the relationship of pre-specified interventions on a specific target outcome and apply a counterfactual framework and statistical techniques to derive causal effects of exposures or interventions from these data. Causal inference is based on a causal diagram, more specifically, a directed acyclic graph (DAG), which encodes the assumptions regarding the causal relations between variables. Depending on the type of confounding and selection bias, traditional statistical methods or more complex g-methods are needed to derive valid causal effects. Besides the correct specification of the DAG and the statistical model, assumptions such as consistency, positivity, and exchangeability must be checked when aiming at causal inference.Health decision science aims for guiding policy decision making regarding health interventions considering and balancing multiple competing objectives of a decision based on data from multiple sources and studies, for example prevalence studies, clinical trials and long-term observational routine effectiveness studies, and studies on preferences and costs. It involves decision analysis, a systematic, explicit and quantitative framework to guide decisions under uncertainty. Decision analyses are based on decision-analytic models to mimic the course of disease as well as aspects and consequences of the intervention in order to quantitatively optimize the decision. Depending on the type of decision problem, decision trees, state-transition models, discrete event simulation models, dynamic transmission models, or other model types are applied. Models must be validated against observed data, and comprehensive sensitivity analyses must be performed to assess uncertainty. Besides the appropriate choice of the model type and the valid specification of the model structure, it must be checked if input parameters of effects can be interpreted as causal parameters in the model. Otherwise results will be biased.Conclusions: Both causal inference and health decision science aim for providing best causal evidence for informed health decision making. The strengths and limitations of both methods differ and a good understanding of both methods is essential for correct application but also for correct interpretation of findings from the described methods. Importantly, decision-analytic modeling should be combined with causal inference when developing guidance and recommendations regarding decisions on health care interventions.

Background: Chemotherapy is often used in the treatment of breast cancer in women. Side effects such as diarrhea, fatigue, hair loss, fever or disturbances in blood formation impair the women’s quality of life. An essential treatment goal of the accompanying mistletoe therapy (MT) used in complementary medicine is to improve the health-related quality of life during cancer therapy.Aim and methods: The HTA report on which this article is based examines the medical efficacy and safety, costs and cost-effectiveness, patient and social aspects, and ethical aspects of MT in women with breast cancer. Systematic reviews were conducted for this purpose. The search period of the literature search ranged from 2004 to October 2020.Results: A total of 2 evidence-based medical guidelines, 3 randomized trials assessing efficacy and 1 additional non-randomized intervention trial, as well as 3 observational studies assessing safety, a cost analysis, 12 cross-sectional studies on patient aspects and 17 articles on ethical evaluation were included. Improvements in health-related quality of life compared to the control group were small to moderate. Due to the high risk of bias in the studies, it is possible that the difference is not caused by MT. One study with a small sample size showed no effect on progression-free survival after 5 years. Studies on the effect of MT on overall survival are lacking. In seven studies, local skin reactions of low and moderate severity were reported in a median of 25% (range 5 to 94%) of patients, and mild to moderate systemic reactions in a median of 2% (range 0 to 8%) of patients. A comparative cost analysis from Germany reported significantly lower medical costs within 5 years after surgery for patients with MT than for patients without MT, but the underlying observational study did not control for systematic bias. With regard to patient aspects, the frequency of use and the reasons for use from the patient’s or practitioner’s point of view were mainly investigated. A median of 25% (range 7 to 46%) of patients with breast cancer and 29% (range 29 to 79%) of treatment providers use MT. The main motivations of patients for use were to reduce side effects, strengthen the immune system and take an active role in the treatment process. Patients felt insufficiently advised. Studies on other aspects are lacking. The ethical evaluation was able to identify 6 overarching themes; the central challenge is the insufficient evidence on efficacy and safety.

Objectives: The prevalence of newborn hearing disorders is 1-3 per 1,000. Crucial for later outcome are correct diagnosis and effective treatment as soon as possible. With BERA and TEOAE low-risk techniques for early detection are available. Universal screening is recommended but not realised in most European health care systems.Aim of the study was to examine the scientific evidence of newborn hearing screening and a comparison of medical outcome and costs of different programmes, differentiated by type of strategy (risk screening, universal screening, no systematical screening). Methods: In an interdisciplinary health technology assessment project all studies on newborn hearing screening detected in a standardized comprehensive literature search were identified and data on medical outcome, costs, and cost-effectiveness extracted. A Markov model was designed to calculate cost-effectiveness ratios. Results: Economic data were extracted from 20 relevant publications out of 39 publications found. In the model total costs for screening of 100,000 newborns with a time horizon of ten years were calculated: 2.0 Mio.€ for universal screening (U), 1.0 Mio.€ for risk screening (R), and 0.6 Mio.€ for no screening (N). The costs per child detected: 13,395€ (U) respectively 6,715€ (R), and 4,125€ (N). At 6 months of life the following percentages of cases are detected: U 72%, R 43%, N 13%. Conclusions: A remarkable small number of economic publications mainly of low methodological quality was found. In our own model we found reasonable cost-effectiveness ratios also for universal screening. Considering the outcome advantages of higher numbers of detected cases a universal newborn hearing screening is recommended.

Objective: The purpose of this health technology assessment (HTA), commissioned by the German Agency for HTA at the German Federal Ministry of Health and Social Security, was to systematically review the evidence on effectiveness and cost-effectiveness of antiviral treatment (AVT) for initial chronic hepatitis C (CHC) and to apply these data in the context of the German health care system. Methods: A systematic literature search was conducted to identify randomised controlled trials (RCTs), meta-analyses, and HTAs that evaluated initial AVT for CHC. A modified version of the German Hepatitis C Model (GEHMO) -- a decision-analytic Markov model -- was used to determine long-term morbidity, life expectancy, quality of life, costs and cost-effectiveness of different treatment strategies. Model parameters were derived from German databases, international RCTs, and a Cochrane Review. Results: Overall, 9 RCTs, 2 HTA reports, 1 Cochrane review, and 2 meta-analyses examining medical effectiveness of antiviral combination therapy, as well as 7 economic evaluations, met the inclusion criteria. These studies indicate that combination therapy with peginterferon plus ribavirin produced the highest sustained virological response rates (54-61%), followed by interferon plus ribavirin with 38-54%, and interferon monotherapy with 11-21%. Based on international cost-effectiveness studies, interferon plus ribavirin is cost-effective compared to interferon monotherapy. No published articles were available regarding cost-effectiveness of peginterferon plus ribavirin. In our decision analysis, these findings were confirmed and the discounted incremental cost-effectiveness ratio for peginterferon plus ribavirin was € 9,800 per quality-adjusted life-year gained compared to interferon monotherapy (as the next best non-dominated strategy). Sensitivity analyses showed robust results across a wide range of model parameters. Conclusions: This HTA suggests that initial combination therapy prolongs life, improves quality of life, and is cost-effective in patients with CHC. Combination of peginterferon and ribavirin is the most effective and efficient treatment strategy among the examined options.

Background: Instrumental variable (IV) analysis provides an alternative set of identification assumptions in the presence of uncontrolled confounding when attempting to estimate causal effects. Our objective was to evaluate the suitability of measures of prescriber preference and calendar time as potential IVs to evaluate the comparative effectiveness of buprenorphine/naloxone versus methadone for treatment of opioid use disorder (OUD). Methods: Using linked population-level health administrative data, we constructed five IVs: prescribing preference at the individual, facility, and region levels (continuous and categorical variables), calendar time, and a binary prescriber's preference IV in analyzing the treatment assignment-treatment discontinuation association using both incident-user and prevalent-new-user designs. Using published guidelines, we assessed and compared each IV according to the four assumptions for IVs, employing both empirical assessment and content expertise. We evaluated the robustness of results using sensitivity analyses. Results: The study sample included 35,904 incident users (43.3% on buprenorphine/naloxone) initiated on opioid agonist treatment by 1585 prescribers during the study period. While all candidate IVs were strong (A1) according to conventional criteria, by expert opinion, we found no evidence against assumptions of exclusion (A2), independence (A3), monotonicity (A4a), and homogeneity (A4b) for prescribing preference-based IV. Some criteria were violated for the calendar time-based IV. We determined that preference in providerlevel prescribing, measured on a continuous scale, was the most suitable IV for comparative effectiveness of buprenorphine/naloxone and methadone for the treatment of OUD. Conclusions: Our results suggest that prescriber's preference measures are suitable IVs in comparative effectiveness studies of treatment for OUD. [ABSTRACT FROM AUTHOR]