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Hiding unhealthy heart outcomes in a low-fat diet trial: the Women's Health Initiative Randomized Controlled Dietary Modification Trial finds that postmenopausal women with established coronary heart disease were at increased risk of an adverse outcome if they consumed a low-fat 'heart-healthy' diet.
Noakes, TD
Open heart. 2021;(2)
Abstract
The Women's Health Initiative Randomized Controlled Dietary Modification Trial (WHIRCDMT) was designed to test whether the US Department of Agriculture's 1977 Dietary Guidelines for Americans protects against coronary heart disease (CHD) and other chronic diseases. The only significant finding in the original 2006 WHIRCDMT publication was that postmenopausal women with CHD randomised to a low-fat 'heart-healthy' diet in 1993 were at 26% greater risk of developing additional CHD events compared with women with CHD eating the control diet. A 2017 WHIRCDMT publication includes data for an additional 5 years of follow-up. It finds that CHD risk in this subgroup of postmenopausal women had increased further to 47%-61%. The authors present three post-hoc rationalisations to explain why this finding is 'inadmissible': (1) only women in this subgroup were less likely to adhere to the prescribed dietary intervention; (2) their failure to follow the intervention diet increased their CHD risk; and (3) only these women were more likely to not have received cholesterol-lowering drugs. These rationalisations appear spurious. Rather these findings are better explained as a direct consequence of postmenopausal women with features of insulin resistance (IR) eating a low-fat high-carbohydrate diet for 13 years. All the worst clinical features of IR, including type 2 diabetes mellitus (T2DM) in some, can be 'reversed' by the prescription of a high-fat low-carbohydrate diet. The Women's Health Study has recently reported that T2DM (10.71-fold increased risk) and other markers of IR including metabolic syndrome (6.09-fold increased risk) were the most powerful predictors of future CHD development in women; blood low-density lipoprotein-cholesterol concentration was a poor predictor (1.38-fold increased risk). These studies challenge the prescription of the low-fat high-carbohydrate heart-healthy diet, at least in postmenopausal women with IR, especially T2DM. According to the medical principle of 'first do no harm', this practice is now shown to be not evidence-based, making it scientifically unjustifiable, perhaps unethical.
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(Outcome) Measure for (Intervention) Measures: A Guide to Choosing the Appropriate Noninvasive Clinical Outcome Measure for Intervention Studies in Celiac Disease.
Singh, P, Silvester, JA, Leffler, D
Gastroenterology clinics of North America. 2019;(1):85-99
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There is an unmet need for diagnostic and treatment interventions for celiac disease. Both clinical trials and real-world studies require careful selection of clinical outcome measures. Often, neither serology nor histology is an appropriate primary outcome. This article reviews various measures of intestinal function and nutrition, patient-reported outcome measures for symptoms and for health-related quality of life, and measures of sickness burden as they apply to intervention studies for celiac disease. A series of case studies is presented to illustrate key considerations in selecting outcome measures for dietary interventions, pharmacologic interventions, and real-world studies.
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Biomarker definitions and their applications.
Califf, RM
Experimental biology and medicine (Maywood, N.J.). 2018;(3):213-221
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Biomarkers are critical to the rational development of medical therapeutics, but significant confusion persists regarding fundamental definitions and concepts involved in their use in research and clinical practice, particularly in the fields of chronic disease and nutrition. Clarification of the definitions of different biomarkers and a better understanding of their appropriate application could result in substantial benefits. This review examines biomarker definitions recently established by the U.S. Food and Drug Administration and the National Institutes of Health as part of their joint Biomarkers, EndpointS, and other Tools (BEST) resource. These definitions are placed in context of their respective uses in patient care, clinical research, or therapeutic development. We explore the distinctions between biomarkers and clinical outcome assessments and discuss the specific definitions and applications of diagnostic, monitoring, pharmacodynamic/response, predictive, prognostic, safety, and susceptibility/risk biomarkers. We also explore the implications of current biomarker development trends, including complex composite biomarkers and digital biomarkers derived from sensors and mobile technologies. Finally, we discuss the challenges and potential benefits of biomarker-driven predictive toxicology and systems pharmacology, the need to ensure quality and reproducibility of the science underlying biomarker development, and the importance of fostering collaboration across the entire ecosystem of medical product development. Impact statement Biomarkers are critical to the rational development of medical diagnostics and therapeutics, but significant confusion persists regarding fundamental definitions and concepts involved in their use in research and clinical practice. Clarification of the definitions of different biomarker classes and a better understanding of their appropriate application could yield substantial benefits. Biomarker definitions recently established in a joint FDA-NIH resource place different classes of biomarkers in the context of their respective uses in patient care, clinical research, or therapeutic development. Complex composite biomarkers and digital biomarkers derived from sensors and mobile technologies, together with biomarker-driven predictive toxicology and systems pharmacology, are reshaping development of diagnostic and therapeutic technologies. An approach to biomarker development that prioritizes the quality and reproducibility of the science underlying biomarker development and incorporates collaborative regulatory science involving multiple disciplines will lead to rational, evidence-based biomarker development that keeps pace with scientific and clinical need.
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Standardizing Clinically Meaningful Outcome Measures Beyond HbA1c for Type 1 Diabetes: A Consensus Report of the American Association of Clinical Endocrinologists, the American Association of Diabetes Educators, the American Diabetes Association, the Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange.
Agiostratidou, G, Anhalt, H, Ball, D, Blonde, L, Gourgari, E, Harriman, KN, Kowalski, AJ, Madden, P, McAuliffe-Fogarty, AH, McElwee-Malloy, M, et al
Diabetes care. 2017;(12):1622-1630
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OBJECTIVE To identify and define clinically meaningful type 1 diabetes outcomes beyond hemoglobin A1c (HbA1c) based upon a review of the evidence, consensus from clinical experts, and input from researchers, people with type 1 diabetes, and industry. Priority outcomes include hypoglycemia, hyperglycemia, time in range, diabetic ketoacidosis (DKA), and patient-reported outcomes (PROs). While priority outcomes for type 1 and type 2 diabetes may overlap, type 1 diabetes was the focus of this work. RESEARCH AND METHODS A Steering Committee-comprising representatives from the American Association of Clinical Endocrinologists, the American Association of Diabetes Educators, the American Diabetes Association, the Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange-was the decision-making body for the Type 1 Diabetes Outcomes Program. Their work was informed by input from researchers, industry, and people with diabetes through Advisory Committees representing each stakeholder group. Stakeholder surveys were used to identify priority outcomes. The outcomes prioritized in the surveys were hypoglycemia, hyperglycemia, time in range, DKA, and PROs. To develop consensus on the definitions of these outcomes, the Steering Committee relied on published evidence, their clinical expertise, and feedback from the Advisory Committees. RESULTS The Steering Committee developed definitions for hypoglycemia, hyperglycemia, time in range, and DKA in type 1 diabetes. The definitions reflect their assessment of the outcome's short- and long-term clinical impact on people with type 1 diabetes. Knowledge gaps to be addressed by future research were identified. The Steering Committee discussed PROs and concluded that further type 1 diabetes-specific development is needed. CONCLUSIONS The Steering Committee recommends use of the defined clinically meaningful outcomes beyond HbA1c in the research, development, and evaluation of type 1 diabetes therapies.
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Efficacy of oral pharmacological treatments in dyskinetic cerebral palsy: a systematic review.
Masson, R, Pagliano, E, Baranello, G
Developmental medicine and child neurology. 2017;(12):1237-1248
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AIM: To evaluate the actual evidence of efficacy of oral pharmacological treatments in the management of dyskinetic cerebral palsy (CP). METHOD A systematic review was performed according to the American Academy for Cerebral Palsy and Developmental Medicine (AACPDM) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology. Articles were searched for in PubMed/MEDLINE, Scopus, Web of Science, Cochrane Library, Database of Reviews of Effectiveness, OTSeeker, Physiotherapy Evidence Database, REHABDATA, and ClinicalTrials.gov. RESULTS Sixteen articles met the eligibility criteria. Eight studies on trihexyphenidyl and two on levodopa showed contradictory results. Low efficacy was reported for diazepam, dantrolene sodium, perphenazine, and etybenzatropine. Tetrabenazine, gabapentin and levetiracetam should be studied in more detail. The updated available evidence does not support any therapeutic algorithm for the management of dyskinetic CP. INTERPRETATION This lack of evidence is partially owing to the inconsistency of classifications of patients and of outcome measures used in the reviewed studies. Further randomized, double-blind, placebo-controlled pharmacological trials, optimized for different age groups, based on valid, reliable, and disease-specific rating scales are strongly needed. Outcome measures should be selected within the framework of the International Classification of Functioning, Disability and Health. WHAT THIS PAPER ADDS Evidence to prove (or disprove) the efficacy of oral drugs in dyskinetic cerebral palsy is low. The most investigated drugs, trihexyphenidyl and levodopa, show contradictory results. Tetrabenazine, levetiracetam, and gabapentin efficacy should be studied in more detail. Lack of evidence is partially due to the inconsistency of classifications and outcome measures used. Outcome measures should be selected within the framework of the International Classification of Functioning, Disability and Health in next clinical trials.
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Outcome Measures for Artificial Pancreas Clinical Trials: A Consensus Report.
Maahs, DM, Buckingham, BA, Castle, JR, Cinar, A, Damiano, ER, Dassau, E, DeVries, JH, Doyle, FJ, Griffen, SC, Haidar, A, et al
Diabetes care. 2016;(7):1175-9
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Research on and commercial development of the artificial pancreas (AP) continue to progress rapidly, and the AP promises to become a part of clinical care. In this report, members of the JDRF Artificial Pancreas Project Consortium in collaboration with the wider AP community 1) advocate for the use of continuous glucose monitoring glucose metrics as outcome measures in AP trials, in addition to HbA1c, and 2) identify a short set of basic, easily interpreted outcome measures to be reported in AP studies whenever feasible. Consensus on a broader range of measures remains challenging; therefore, reporting of additional metrics is encouraged as appropriate for individual AP studies or study groups. Greater consistency in reporting of basic outcome measures may facilitate the interpretation of study results by investigators, regulatory bodies, health care providers, payers, and patients themselves, thereby accelerating the widespread adoption of AP technology to improve the lives of people with type 1 diabetes.
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Cardiometabolic Risks in Schizophrenia and Directions for Intervention, 2: Nonpharmacological Interventions.
Andrade, C
The Journal of clinical psychiatry. 2016;(8):e964-7
Abstract
Patients with schizophrenia have increased prevalence rates for many cardiometabolic risks, including the metabolic syndrome, and an increased risk of adverse cardiovascular events, including mortality. Behavioral interventions such as diet and exercise (separately and together) improve physical health outcomes in the general population. There are no studies on dietary guidance as a sole behavioral intervention for patients with schizophrenia. A meta-analysis found that exercise as a sole behavioral intervention does not result in meaningful physical or mental health gains in patients with major mental illness. Another meta-analysis found that combined diet and exercise, along with other behavioral elements, was associated with statistically significant but modest weight reduction (mean = 3.14 kg) in the short to intermediate term, but with no other cardiometabolic risk factor benefits. A large, well-supervised, pragmatic, 1-year randomized controlled trial found that behavioral interventions were not associated with health gains on a 10-year cardiovascular risk index, or on a large range of indices of physical and mental health. An added concern is that patients with schizophrenia are poorly motivated for behavioral interventions and show poor participation in such interventions. Barriers, and means of overcoming these barriers, have been identified for the implementation of behavioral programs to improve physical health in patients with serious mental illness. It remains to be demonstrated, however, that behavioral intervention programs consistently improve cardiovascular health indices in patients with schizophrenia and other major mental illnesses.
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Understanding the metabolic and health effects of low-calorie sweeteners: methodological considerations and implications for future research.
Sylvetsky, AC, Blau, JE, Rother, KI
Reviews in endocrine & metabolic disorders. 2016;(2):187-94
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Consumption of foods, beverages, and packets containing low-calorie sweeteners (LCS) has increased markedly across gender, age, race/ethnicity, weight status, and socio-economic subgroups. However, well-controlled intervention studies rigorously evaluating the health effects of LCS in humans are limited. One of the key questions is whether LCS are indeed a beneficial strategy for weight management and prevention of obesity. The current review discusses several methodological considerations in the design and interpretation of these studies. Specifically, we focus on the selection of study participants, inclusion of an appropriate control, importance of considering habitual LCS exposure, selection of specific LCS, dose and route of LCS administration, choice of study outcomes, and the context and generalizability of the study findings. These critical considerations will guide the design of future studies and thus assist in understanding the health effects of LCS.
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The involvement of young people in school- and community-based noncommunicable disease prevention interventions: a scoping review of designs and outcomes.
Jourdan, D, Christensen, JH, Darlington, E, Bonde, AH, Bloch, P, Jensen, BB, Bentsen, P
BMC public health. 2016;(1):1123
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BACKGROUND Since stakeholders' active engagement is essential for public health strategies to be effective, this review is focused on intervention designs and outcomes of school- and community-based noncommunicable disease (NCD) prevention interventions involving children and young people. METHODS The review process was based on the principles of scoping reviews. A systematic search was conducted in eight major databases in October 2015. Empirical studies published in English, French, Portuguese, and Spanish were considered. Five selection criteria were applied. Included in the review were (1) empirical studies describing (2) a health intervention focused on diet and/or physical activity, (3) based on children's and young people's involvement that included (4) a relationship between school and local community while (5) providing explicit information about the outcomes of the intervention. The search provided 3995 hits, of which 3253 were screened by title and abstract, leading to the full-text screening of 24 papers. Ultimately, 12 papers were included in the review. The included papers were analysed independently by at least two reviewers. RESULTS Few relevant papers were identified because interventions are often either based on children's involvement or are multi-setting, but rarely both. Children were involved through participation in needs assessments, health committees and advocacy. School-community collaboration ranged from shared activities, to joint interventions with common goals and activities. Most often, collaboration was school-initiated. Most papers provided a limited description of the outcomes. Positive effects were identified at the organisational level (policy, action plans, and healthy environments), in adult stakeholders (empowerment, healthy eating) and in children (knowledge, social norms, critical thinking, and health behaviour). Limitations related to the search and analytical methods are discussed. CONCLUSION There are very few published studies on the effectiveness of interventions based on children's involvement in school- and community-based NCD prevention programmes. However, interventions with these characteristics show potential benefits, and the merits of complex multi-setting approaches should be further explored through intervention-based studies assessing their effectiveness and identifying which components contribute to the observed outcomes.
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Outcomes in Cochrane systematic reviews addressing four common eye conditions: an evaluation of completeness and comparability.
Saldanha, IJ, Dickersin, K, Wang, X, Li, T
PloS one. 2014;(10):e109400
Abstract
INTRODUCTION Choice of outcomes is critical for clinical trialists and systematic reviewers. It is currently unclear how systematic reviewers choose and pre-specify outcomes for systematic reviews. Our objective was to assess the completeness of pre-specification and comparability of outcomes in all Cochrane reviews addressing four common eye conditions. METHODS We examined protocols for all Cochrane reviews as of June 2013 that addressed glaucoma, cataract, age-related macular degeneration (AMD), and diabetic retinopathy (DR). We assessed completeness and comparability for each outcome that was named in ≥ 25% of protocols on those topics. We defined a completely-specified outcome as including information about five elements: domain, specific measurement, specific metric, method of aggregation, and time-points. For each domain, we assessed comparability in how individual elements were specified across protocols. RESULTS We identified 57 protocols addressing glaucoma (22), cataract (16), AMD (15), and DR (4). We assessed completeness and comparability for five outcome domains: quality-of-life, visual acuity, intraocular pressure, disease progression, and contrast sensitivity. Overall, these five outcome domains appeared 145 times (instances). Only 15/145 instances (10.3%) were completely specified (all five elements) (median = three elements per outcome). Primary outcomes were more completely specified than non-primary (median = four versus two elements). Quality-of-life was least completely specified (median = one element). Due to largely incomplete outcome pre-specification, conclusive assessment of comparability in outcome usage across the various protocols per condition was not possible. DISCUSSION Outcome pre-specification was largely incomplete; we encourage systematic reviewers to consider all five elements. This will indicate the importance of complete specification to clinical trialists, on whose work systematic reviewers depend, and will indirectly encourage comparable outcome choice to reviewers undertaking related research questions. Complete pre-specification could improve efficiency and reduce bias in data abstraction and analysis during a systematic review. Ultimately, more completely specified and comparable outcomes could make systematic reviews more useful to decision-makers.