Methodological considerations, such as directed acyclic graphs, for studying “acute on chronic” disease epidemiology: Chronic obstructive pulmonary disease example

ObjectiveAcute exacerbations of chronic disease are ubiquitous in clinical medicine, and thus far, there has been a paucity of integrated methodological discussion on this phenomenon.Study Design and SettingWe use acute exacerbations of chronic obstructive pulmonary disease as an example to emphasize key epidemiological and statistical issues for this understudied field in clinical epidemiology.ResultsDirected acyclic graphs are a useful epidemiological tool to explain the differential effects of risk factor on health outcomes in studies of acute and chronic phases of disease. To study the pathogenesis of acute exacerbations of chronic disease, case-crossover design and time-series analysis are well-suited study designs to differentiate acute and chronic effect. Modeling changes over time and setting appropriate thresholds are important steps to separate acute from chronic phases of disease in serial measurements. In statistical analysis, acute exacerbations are recurrent events, and some individuals are more prone to recurrences than others. Therefore, appropriate statistical modeling should take into account intraindividual dependence. Finally, we recommend the use of “event-based” number needed to treat (NNT) to prevent a single exacerbation instead of traditional patient-based NNT.ConclusionAddressing these methodological challenges will advance research quality in acute on chronic disease epidemiology.     

Challenges in the Development and Reimbursement of Personalized Medicine—Payer and Manufacturer Perspectives and Implications for Health Economics and Outcomes Research: A Report of the ISPOR Personalized Medicine Special Interest Group

BackgroundPersonalized medicine technologies can improve individual health by delivering the right dose of the right drug to the right patient at the right time but create challenges in deciding which technologies offer sufficient value to justify widespread diffusion. Personalized medicine technologies, however, do not neatly fit into existing health technology assessment and reimbursement processes.ObjectivesIn this article, the Personalized Medicine Special Interest Group of the International Society for Pharmacoeconomics and Outcomes Research evaluated key development and reimbursement considerations from the payer and manufacturer perspectives.MethodsFive key areas in which health economics and outcomes research best practices could be developed to improve value assessment, reimbursement, and patient access decisions for personalized medicine have been identified.ResultsThese areas are as follows: 1 research prioritization and early value assessment, 2 best practices for clinical evidence development, 3 best practices for health economic assessment, 4 addressing health technology assessment challenges, and 5 new incentive and reimbursement approaches for personalized medicine.ConclusionsKey gaps in health economics and outcomes research best practices, decision standards, and value assessment processes are also discussed, along with next steps for evolving health economics and outcomes research practices in personalized medicine.     

Challenges and Solutions for the Benefit Assessment of Tumor-Agnostic Therapies in Germany

ObjectivesPrecision medicine is increasingly important in cancer treatment. Tumor-agnostic therapies are used regardless of tumor entity because they target specific biomarkers in tumors. In Germany, the benefit assessment of oncological pharmaceuticals has traditionally been entity specific. Thus, the assessment of tumor-agnostic therapies leaves stakeholders with various challenges. Our aim was to systematically identify challenges and possible solutions for the benefit assessment of therapies in tumor-agnostic indications using a 2-step sequential qualitative approach.MethodsTo identify relevant challenges, we conducted qualitative interviews with different stakeholders who were involved in previous benefit assessments of tumor-agnostic therapies in Germany. To identify possible solutions for these challenges, we systematically searched MEDLINE, Embase, and the websites of European health technology assessment bodies for relevant literature.ResultsWe identified 9 categories of challenges of which the following were deemed particularly relevant: the absence of direct comparative studies, challenges regarding the use of basket studies and indirect comparisons, challenges in determining the appropriate comparative therapy in a tumor-agnostic indication, and challenges on the system side. Seven categories of solutions were identified, including an increased use of real-world evidence, making conditional decisions in the context of systematic reassessments, splitting the field of application, and finding (new) ways to design and analyze basket studies.ConclusionA range of possible solutions, which can help to meet the identified challenges in Germany, have been found. Future research should investigate the acceptance and feasibility of these solutions.     

Contingency management for substance use disorders in Spain: Implications for research and practice

ObjectiveWe provide a narrative review of published studies evaluating voucher-based contingency management (CM) treatment for cocaine, nicotine and cannabis use disorders in Spain and discuss the concerns and future challenges.MethodPublished studies between 2008 and 2015 that evaluated the impact of incentives for SUD in Spain and included an appropriate control or comparison condition were identified and reviewed.ResultsAdding voucher-based CM to standard treatments obtained better treatment retention and cocaine abstinence than standard care alone. CM also improved psychosocial functioning. Economic status or depressive symptoms did not affect the results of CM treatment for cocaine dependence. The addition of a CM protocol to cognitive behavioral treatment (CBT) also improved treatment effectiveness for smoking cessation. Available data on the effect of CM on cannabis use disorders (CUD) with young people did not allow confirmation of its superiority to date.ConclusionThe research conducted to date in Spain confirms and expands the findings of studies conducted in the US supporting the effectiveness of CM in the context of community settings with cocaine- and nicotine-dependents. However, CM has not yet been readily adopted into general clinical practice in Spain or the rest of Europe. The limited effectiveness of CM for CUD is likely due to the scarcity of data and may change with more studies, taking into account recent research on this topic in the US. Continued efforts are warranted to further develop and disseminate incentive-based treatments for SUD across clinical settings and populations in Spain.     

Methods for assessing the cost-effectiveness of public health interventions: Key challenges and recommendations

RationaleIncreasing attention is being given to the evaluation of public health interventions. Methods for the economic evaluation of clinical interventions are well established. In contrast, the economic evaluation of public health interventions raises additional methodological challenges. The paper identifies these challenges and provides suggestions for overcoming them.MethodsTo identify the methodological challenges, five reviews that explored the economics of public health were consulted. From these, four main methodological challenges for the economic evaluation of public health interventions were identified. A review of empirical studies was conducted to explore how the methodological challenges had been approached in practice and an expert workshop convened to discuss how they could be tackled in the future.ResultsThe empirical review confirmed that the four methodological challenges were important. In all, 154 empirical studies were identified, covering areas as diverse as alcohol, drug use, obesity and physical activity, and smoking. However, the four methodological challenges were handled badly, or ignored in most of the studies reviewed.DiscussionThe empirical review offered few insights into ways of addressing the methodological challenges. The expert workshop suggested a number of ways forward for overcoming the methodological challenges.ConclusionAlthough the existing empirical literature offers few insights on how to respond to these challenges, expert opinion suggests a number of ways forward. Much of what is suggested here has not yet been applied in practice, and there is an urgent need both for pilot studies and more methodological research.     

Gordon Dixon,protamines, and the atypical patterns of gene expression in spermatogenic cells

ABSTRACT

Gordon Dixon’s pioneering work on the replacement of histones by protamines during spermatogenesis inspired research as recombinant DNA became widely used to analyze gene expression in mammalian spermatogenic cells. The impact of recombinant DNA began immediately with the identification of mouse protamine 1 as a haploid-expressed mRNA, resolving a decades-long controversy whether gene expression in haploid spermatogenic cells distorts transmission of alleles to progeny. Numerous insights into the biology of spermatogenesis followed as the sequences of many mRNAs revealed that the patterns of gene expression in spermatogenic cells are astonishingly different from those in other cells in the mammalian body. Studies of these phenomena have generated fundamental insights across reproductive, molecular and evolutionary biology.

Abbreviations: PRM1: protamine 1; PRM2: protamine 2; TCE: translation control element     

Imprisonment, alcohol dependence and risk of delusional disorder: a cross-sectional study

BackgroundCompared to the general population, an excess of psychotic illnesses, major depression and dependence disorders among prisoners has been reported. However, the impact of prison on detainees’ psychopathology has rarely been studied.ObjectiveTo determine the mental disorders liable to develop or regress on entry into prison and over time.MethodTwo samples of French prisoners detained in local prisons were interviewed using the same methodology. The first sample consisted of 267 new arrivals. The second was a random sample of 450 prisoners. Diagnoses were assessed using a thorough methodology: each prisoner was interviewed for approximately 2 hours by two clinicians. One of the clinicians used a structured clinical interview, which generates DSM IV diagnoses (MINI plus v 5.0); the second completed the procedure with an open clinical interview. The final DSM IV diagnoses were obtained as a consensus between the two approaches. Multilevel logistic regressions were used to take into account potential confounders.ResultsPrevalence rates of mental disorders were substantially higher in prison even for the sample of newcomers (major depression disorder: 24.7%, substance dependence: 17.6% and schizophrenia: 4.1%). Alcohol dependence disorder was significantly more frequent in the sample of newcomers (OR 1.84 [1.01–3.51]). No significant difference was evidenced between samples for substance dependence disorder. Psychotic disorders were significantly less frequent at entry into prison, particularly delusional disorder (OR 0.29 [0.08–0.98]).ConclusionThis study shows the contrasted potential effects of prison on psychopathology: alcohol dependence disorders were significantly more frequent for the newcomers, while the frequency of delusional disorders was lower. This evidence is arguing in favour of the validity of the old concept: prison psychosis. Moreover, prisoners should receive relevant help from clinicians to cope with these disorders.     

Recent applications of DNA microarray technology to toxicology and ecotoxicology

Gene expression is a unique way of characterizing how cells and organisms adapt to changes in the external environment. The measurements of gene expression levels upon exposure to a chemical can be used both to provide information about the mechanism of action of the toxicant and to form a sort of "genetic signature" for the identification of toxic products. The development of high-quality, commercially available gene arrays has allowed this technology to become a standard tool in molecular toxicology. Several national and international initiatives have provided the proof-of-principle tests for the application of gene expression for the study of the toxicity of new and existing chemical compounds. In the last few years the field has progressed from evaluating the potential of the technology to illustrating the practical use of gene expression profiling in toxicology. The application of gene expression profiling to ecotoxicology is at an earlier stage, mainly because of the the many variables involved in analyzing the status of natural populations. Nevertheless, significant studies have been carried out on the response to environmental stressors both in model and in nonmodel organisms. It can be easily predicted that the development of stressor-specific signatures in gene expression profiling in ecotoxicology will have a major impact on the ecotoxicology field in the near future. International collaborations could play an important role in accelerating the application of genomic approaches in ecotoxicology.     

Evaluating the Value for Money of Precision Medicine from Early Cycle to Market Access: A Comprehensive Review of Approaches and Challenges

ObjectivesThis study aimed to perform a comprehensive review of modeling approaches and methodological and policy challenges in the economic evaluation (EE) of precision medicine (PM) across clinical stages.MethodsFirst, a systematic review was performed to assess the approaches of EEs in the past 10 years. Next, a targeted review of methodological articles was conducted for methodological and policy challenges in performing EEs of PM. All findings were synthesized into a structured framework that focused on patient population, Intervention, Comparator, Outcome, Time, Equity and ethics, Adaptability and Modeling aspects, named the “PICOTEAM” framework. Finally, a stakeholder consultation was conducted to understand the major determinants of decision making in PM investment.ResultsIn 39 methodological articles, we identified major challenges to the EE of PM. These challenges include that PM applications involve complex and evolving clinical decision space, that clinical evidence is sparse because of small subgroups and complex pathways in PM settings, a one-time PM application may have lifetime or intergenerational impacts but long-term evidence is often unavailable, and that equity and ethics concerns are exceptional. In 275 EEs of PM, current approaches did not sufficiently capture the value of PM compared with targeted therapies, nor did they differentiate Early EEs from Conventional EEs. Finally, policy makers perceived the budget impact, cost savings, and cost-effectiveness of PM as the most important determinants in decision making.ConclusionsThere is an urgent need to modify existing guidelines or develop a new reference case that fits into the new healthcare paradigm of PM to guide decision making in research and development and market access.     

Obesity,Akkermansia muciniphila,and Proton Pump Inhibitors: Is there a Link?

ObjectiveThe gut bacterium Akkermansia muciniphila (A. muciniphila), has been linked to body composition and metabolism. However, the role of lifestyle factors and medication use in these relationships has not been considered. This study aimed to assess the relative abundance of A. muciniphila in participants and investigate its association with obesity, with consideration of potential confounding factors.MethodsParticipants included 158 men of the Geelong Osteoporosis Study with dual-energy X-ray absorptiometry data, 16S rRNA gene bacterial profiling of stool samples, and lifestyle data. The relative abundance of A. muciniphila was estimated from total sequence reads, while obesity status was quantified by fat mass index (FMI, kg/m²).ResultsIn this cohort (66 ± 12 yr, mean ± SD), the most common medications were proton pump inhibitors (PPIs) (28%), and these were associated with both high FMI and decreased abundance of A. muciniphila. Before and after adjustments for PPIs, participants with substantial A. muciniphila (abundance ≥0.1%, n = 94) compared to very low (abundance <0.1%, n = 64), had lower FMI (adjusted −1.33 (95%CI −2.30, −0.36) kg/m², p = 0.007).ConclusionsIn this sample, relative abundance of A. muciniphila was inversely associated with high FMI, independent of PPI use. The relationship between obesity, reflux medication, and the gut microbiome warrants further investigation.     

Perceptions,professional responsibility and management experiences of patients with alcohol,tobacco and opioid use disorder by residents in general practice and teaching general practitioners

BackgroundSubstance use disorders (SUDs) are based on pathophysiological mechanisms common to all psychoactive substances. However, general practitioners (GPs) hold different views depending on the substance in question.ObjectivesTo determine whether the perceptions that teaching GPs and final-year residents in general practice have of patients with a SUD vary according to the substance involved and explore their professional responsibility and management experiences.MethodsA cross-sectional observational study was carried out by asking residents and teaching GPs from eight faculties of medicine about their perceptions, professional responsibility and management experience of patients with tobacco, alcohol and opioid use disorders, using an online questionnaire between June and September 2017.ResultsThe responses of 238 teaching GPs (mean age 50 years SD 3.5; 58% men) and 327 residents (mean age 28 years SD 9.9; 67% women) were analysed (response rates: 9 and 15% respectively). Tobacco smokers were considered to be more responsible for their acts than the other users. Teaching GPs and residents considered that it was their responsibility to discuss substance use. They did not feel able to manage alcohol and opioid use disorders. Tobacco cessation was mainly managed alone (78%). The results were quite similar among teaching GPs and residents.ConclusionThe majority of practitioners had no difficulty managing smoking cessation. During the management of alcohol and particularly opioid use disorders, practitioners did not feel competent. The gap between their perceived responsibility and competencies should be addressed by training and promoting collaborative care.     

Identifying the barriers and perceptions of non-Hispanic black and Hispanic/Latino persons with uncontrolled type 2 diabetes for participation in a home Telemonitoring feasibility study: a quantitative analysis of those who declined participation,withdrew or were non-adherent

ABSTRACT

Objectives: Type 2 Diabetes Mellitus and its complications disproportionately affect non-Hispanic blacks and Hispanic/Latinos more than non-Hispanic whites. These disparities stem from complex interactions between biological, behavioral and socioeconomic factors. In recent years, telemedicine has been used to manage Type 2 Diabetes; however limited recruitment and retention of black and Hispanic/Latino patients into clinical trials exploring the use of telemedicine have necessitated the elucidation of their perceptions regarding participation in such trials. This study investigated patient-reported reasons for declining participation, prematurely terminating participation or demonstrating poor adherence to the study protocol in an ongoing randomized clinical trial, ‘Feasibility of Telehealth Management of Diabetes Mellitus type 2 (T2DM) in Black and Hispanic Minority Patients’.

Design: Semi-structured interviews comprised of open-ended questions and prompts were conducted by telephone to gauge patients’ actual and perceived challenges to participating in the trial and using telemedicine to manage their diabetes. Data were collated with that of the original clinical trial and subsequently content analyzed for overarching themes and trends.

Results: Eight semi-structured interviews were completed telephonically. Themes that emerged from analysis included disinterest (47%), inconvenience (33%), lack of perceived benefit (13%), lack of awareness of diabetes diagnosis (7%) and perceived lack of ability to fully participate in the study (7%).

Conclusion: Adoption of telemedicine to help minority patients manage diabetes holds promise but is limited by patient factors such as disinterest, inconvenience and lack of perceived benefit. Greater awareness and understanding of these issues will be critical as we strive for greater health equity in disparity patients with uncontrolled diabetes.     

Systems medicine 2030: A Delphi study on implementation in the German healthcare system

IntroductionSystems medicine is based on approaches taken from systems biology, omics research, bio-informatics and network theory. It promises to facilitate a better understanding of the causes of diseases, detection at an earlier stage, and the use of tailor-made approaches to prevention and therapy. This study provides information on how systems medicine could be incorporated into the German healthcare system.MethodsIn a Policy Delphi, consensus and divergence was elicited on whether experts believed systems medicine could be incorporated into the German healthcare system by 2030. Additionally, factors that could influence the implementation process were analysed. 11 theses on potential systems medicine developments and 193 arguments on influencing factors were evaluated. Experts from health and health-related fields were selected using “purposive sampling”.ResultsThe experts interviewed expressed their trust in the provision of a legal-political framework, though they remained uncertain as to whether the necessary social discourse on the ethical and cultural questions surrounding systems medicine would occur. They do not (currently) expect systems medicine to be implemented by 2030.ConclusionSystems medicine is currently regarded as a visionary concept. As such, it would be premature to attempt to judge the success of the translation process at this stage. The results can help with the identification of the challenges involved in implementation, and the action required to achieve this aim.     

Integrating breast cancer genetics into clinical practice

Breast cancer prognosis and treatment is guided by traditional clinicopathological parameters and individual molecular markers. Despite the remarkable advances in our scientific understanding of breast cancer genetics, the impact of such information on medical care has, to date, been modest. Although the use of simple genetics is already in vogue in clinical practice, the concept of molecular profiling and multiparameter gene classifiers was raised after the introduction of the high-throughput gene expression microarrays. This technology, in addition to highlighting the molecular heterogeneity of breast cancer, has led to the development of prognostic and predictive gene signatures. Studies are underway to assess the clinical validity and clinical utility of these multigene assays and their incorporation into clinical practice. This article reviews the current status and projected future use of genetics and genomics in breast cancer management and their impact on the refinement of risk stratification to permit individualized and patient-tailored therapy. Limitations based on our current scientific understanding and realistic expectations are also explored.     

The diagnosis of acute myeloid leukaemia enhanced by using DNA microarrays

Recently, two studies have shown that the use ofgene-expression profiling using DNA microarrays or DNA chips may improve the classification of acute myeloid leukaemia (AML). In both studies, cluster analyses based on the molecular signatures defined known subgroups as well as novel subgroups of AML. Chromosomal lesions, mutations, and abnormal gene expression with prognostic value determined the clustering. In fact, gene-expression profiling recognized leukaemias with certain chromosomal aberrations that had been missed by routine cytogenetics. Thus, gene-expression profiling allows a comprehensive classification of AML that includes previously-identified genetically-defined as well as novel prognostically-relevant subgroups. One comprehensive DNA chip may in the future replace a variety of cytogenetic, immunological and molecular techniques that are currently used in combination.