A shared latent space matrix factorisation method for recommending new trial evidence for systematic review updates.

BACKGROUND: Clinical trial registries can be used to monitor the production of trial evidence and signal when systematic reviews become out of date. However, this use has been limited to date due to the extensive manual review required to search for and screen relevant trial registrations. Our aim was to evaluate a new method that could partially automate the identification of trial registrations that may be relevant for systematic review updates. MATERIALS AND METHODS: We identified 179 systematic reviews of drug interventions for type 2 diabetes, which included 537 clinical trials that had registrations in ClinicalTrials.gov. Text from the trial registrations were used as features directly, or transformed using Latent Dirichlet Allocation (LDA) or Principal Component Analysis (PCA). We tested a novel matrix factorisation approach that uses a shared latent space to learn how to rank relevant trial registrations for each systematic review, comparing the performance to document similarity to rank relevant trial registrations. The two approaches were tested on a holdout set of the newest trials from the set of type 2 diabetes systematic reviews and an unseen set of 141 clinical trial registrations from 17 updated systematic reviews published in the Cochrane Database of Systematic Reviews. The performance was measured by the number of relevant registrations found after examining 100 candidates (recall@100) and the median rank of relevant registrations in the ranked candidate lists. RESULTS: The matrix factorisation approach outperformed the document similarity approach with a median rank of 59 (of 128,392 candidate registrations in ClinicalTrials.gov) and recall@100 of 60.9% using LDA feature representation, compared to a median rank of 138 and recall@100 of 42.8% in the document similarity baseline. In the second set of systematic reviews and their updates, the highest performing approach used document similarity and gave a median rank of 67 (recall@100 of 62.9%). CONCLUSIONS: A shared latent space matrix factorisation method was useful for ranking trial registrations to reduce the manual workload associated with finding relevant trials for systematic review updates. The results suggest that the approach could be used as part of a semi-automated pipeline for monitoring potentially new evidence for inclusion in a review update.

Healthy Lifestyle Pattern is Protective Against 30-Yr Cancer Incidence in Men and Women: A Cohort Study.

OBJECTIVES: Investigate associations of healthier behaviors with 30-yr cancer incidence. SUBJECTS/METHODS: In 1982, 632 healthy men and women (ages 40-70) were interviewed for nutritional habits using a Food Frequency Questionnaire and a 24-h physical activity questionnaire. Blood pressure, weight, and height were measured, and blood was drawn for biochemical profiles. Thirteen and four subjects were excluded due to cancer diagnosis ≤1 yr from recruitment and extreme values of reported total daily calorie intake, respectively. RESULTS: During a mean follow-up of 24.2 yr, 146 cancer incident patients (23.7%) were documented. Total cancer risk was 38% lower in the medium vegetable intake tertile [adjusted hazards ratio (HR) = 0.62, 95%confidence interval (CI): 0.40-0.95], and 66% higher in the medium fruit intake tertile (adjusted HR = 1.66, 95%CI: 1.08-2.55) compared to the lowest tertile. The risk of gastrointestinal cancers was 3 times greater for the highest, compared to the lowest, dairy consumption tertile (HR = 3.06, 95%CI: 1.01-9.23). "Healthy lifestyle" (normal BMI, never smoked, consuming high levels of dietary fiber and vegetables, and more physically active) reduced overall cancer risk (adjusted HR = 0.63, 95%CI: 0.44-0.91) as compared to the rest of the cohort. CONCLUSIONS: Our findings reinforce the importance of lifestyle-related factors, which are relatively low-cost and may contribute to reduction in the burden of malignant diseases.

Factors associated with attempting and succeeding in smoking cessation following a National Tobacco Control Plan: Analysis of two nationwide surveys (2010 and 2017).

INTRODUCTION: Lower rates of smoking cessation among disadvantaged groups contribute to widening health-disparities. With this recognition, in 2010 free-of-charge/subsidized smoking cessation services became available to all Israeli residents through the not-for-profit health plans. METHODS: Based on two cross-sectional National Social Surveys, data on adult ever-smokers were used (n = 2,998 in 2010 and 2,859 in 2017). The outcome variable comprised three categories: no quit attempt, unsuccessful quit attempt and successful quit attempt. Changes over-time and demographic, socioeconomic, health- and smoking-related factors associated with quitting attempts and success were tested in the pooled sample, using multivariable multinomial logistic regression models. RESULTS: The pooled sample of the two surveys included 2,611 participants (44.2%) who were successful quitters, 1,941 (32.7%) who reported an unsuccessful quit attempt, and 1,305 (23.1%) smokers who did not attempt to quit. Compared to 2010, ever-smokers in 2017 were less likely to report an unsuccessful quit attempt (adjusted OR = 0.81, 95%CI: 0.70-0.94). The likelihood of successfully quitting was similar in both surveys. Older age and self-reported health problem were associated with higher likelihood of quitting attempt. Meeting living expenses, being overweight/obese, engaging in physical activity and heavy smoking were associated with higher likelihood of successful smoking cessation; while environmental tobacco exposure was associated with 43% lower likelihood of successful cessation. Finally, there was an interaction between education and ethnicity. Higher education level was associated with a greater likelihood both to attempt to quit smoking and to succeed among Jewish participants, while the opposite phenomenon was observed among Arab smokers. CONCLUSIONS: Despite the availability of subsidized smoking cessation services, social disparities in smoking cessation rates persist. Efforts should focus on proactively reaching subpopulations with low cessation rates, using tailored strategies for successful smoking cessation. Promoting smoke free homes and workplaces should be prioritized.

Emulated Trial for Discharge Prescription of Guideline-Directed Medical Therapy and 15-Year Survival After Coronary Artery Bypass Graft Surgery.

OBJECTIVES: To explore admission and discharge prescription rates of guideline-directed medical therapy (GDMT), defined as aggregate antiplatelet agents, statins, and ß-blockers, after coronary artery bypass graft (CABG) surgery and to reveal its association with long-term survival. PATIENTS AND METHODS: This is a prospective cohort study-based emulated trial of patients undergoing elective or semi-elective isolated CABG surgery in 7 cardiothoracic units in Israel from January 1, 2004, to December 31, 2007, and followed up until December 31, 2020, for all-cause mortality. RESULTS: Only 59.2% of 968 patients (n=573) were discharged on GDMT after CABG surgery. Admission GDMT use conferred a 7 times greater likelihood of discharge GDMT prescription (odds ratio, 7.07; 95% CI, 5.04 to 9.91; P<.001), with no sex differences observed. After applying inverse probability of treatment weighting, baseline characteristics were well balanced between groups. During a median follow-up of 13.7 years, a Cox regression model with propensity score-adjusted inverse probability of treatment weighting revealed lower mortality in patients with discharge GDMT prescription who underwent CABG surgery than in their counterparts (hazard ratio, 0.75; 95% CI, 0.60 to 0.93; P=.008). CONCLUSION: The use of aggregate GDMT before surgery conferred a greater likelihood of GDMT prescription upon discharge, which, in turn, is associated with better long-term survival. Educational efforts of pertinent medical professionals are needed to minimize preventive treatment gaps. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00356863.

Polypharmacy is differentially associated with 20-year mortality among community-dwelling elderly women and men: The Israel Glucose Intolerance, Obesity and Hypertension cohort study.

BACKGROUND: Elderly individuals are characterized by multimorbidity and high medication intake, entailing risks for adverse events. We examined the overall and sex-specific association of polypharmacy (≥5 drugs concurrently) with 20-year mortality among community-dwelling older adults. METHODS: Survivors of the longitudinal Israel Study of Glucose Intolerance, Obesity, and Hypertension underwent extensive evaluation during 1999-2004, and were followed-up for all-cause mortality until 2019. Cox regression examined association of polypharmacy with all-cause mortality. RESULTS: Data included 1210 participants (mean baseline age 72.9 ± 7.4 years, 53% females), 50.7% of them died over a median follow-up of 12.8 years. Women received a higher mean number of drugs (4.3 vs 3.5; p < 0.0001), were twice more likely to take vitamins, and had higher comorbidity. Polypharmacy prevalence was 38.3%, and more frequent with age, female sex, European-American origin, sedentary lifestyle and poor self-rated health. Polypharmacy was independently associated with mortality in women only (HR=1.41, 95%CI:1.05-1.89). An interaction was found with sex (p = 0.045). CONCLUSIONS: Polypharmacy was more prevalent in older women than men and associated with increased 20-year mortality in women only. Sex-specific adaptation of guidelines for appropriate drug use among community-dwelling older adults is warranted.

Pediatric Trials for Cancer Therapies With Targets Potentially Relevant to Pediatric Cancers.

The Research to Accelerate Cures and Equity (RACE) for Children Act was enacted in 2017 to authorize the US Food and Drug Administration (FDA) to require pediatric studies for new cancer drugs that have a molecular target relevant to the growth or progression of a pediatric cancer. To assess the possible scope of this new policy, we examined all 78 adult cancer drugs approved by the FDA from 2007 to 2017. Only 17 (21.8%) drugs received any pediatric labeling information. Based on the FDA's Pediatric Molecular Target List, we found that the RACE Act could have increased the proportion of cancer drugs potentially subject to pediatric study requirements from 0% to 78.2%. However, the actual effect of the legislation will depend on how often regulators require pediatric trials and on timely completion of such trials.

Factors associated with disparities in out-of-pocket expenditure on dental care: results from two cross-sectional national surveys.

BACKGROUND: Socioeconomic differences in oral health and dental care utilization are a persistent problem in many high-income countries. We evaluated demographic, geographic and socioeconomic factors associated with disparities in households' out-of-pocket expenditure (OOPE) on dental care, and the effect of ongoing dental health reform on these disparities. METHODS: This cross-sectional analysis used data collected in two Israeli Household Expenditure Surveys conducted in 2014 and 2018. OOPE for dental care was estimated using a two-part multivariable model. A logistic regression was used to examine the likelihood of reporting any OOPE, and a log-transformed linear regression model examined the level of expenditure among those who reported any OOPE. RESULTS: In 2018, OOPE on dental care accounted for 22% of total health expenditure for all households, whereas among those who reported dental OOPE it reached 43%. Households with children up to age 14 years reported lower OOPE, regardless of ownership of supplementary health insurance. Owning supplementary health insurance had a heterogeneous effect on the level of OOPE, with a significant increase among those with 0-8 years of education, compared to households without such insurance, but not among those of higher educational level. In 2014, Arab ethnic minority and residence in the country periphery were associated with a greater likelihood for any OOPE and higher amounts of OOPE on dental care. While the gaps between Jewish and Arab households persisted into 2018, those between peripheral and non-peripheral localities seem to have narrowed. CONCLUSIONS: The burden of dental OOPE on Israeli households remains heavy and some disparities still exist, even after the implementation of the dental health reform. Expanding the dental health reform and addressing barriers to preventive dental care, especially among Arabs and those of lower educational level, may help in reducing households' private expenses on dental care.

The timing and frequency of trial inclusion in systematic reviews of type 2 diabetes drugs was associated with trial characteristics.

OBJECTIVE: To determine whether certain trial characteristics are associated with faster or more frequent inclusion in systematic reviews for drug interventions in type 2 diabetes. STUDY DESIGN AND SETTING: We examined trials included in systematic reviews published between January 1, 2007 and January 1, 2017. Primary outcomes were time between trial publication and first inclusion in a systematic review and frequency of inclusion in systematic reviews over the study period. Multivariable Cox proportional hazards and regression models quantified associations with funding source, number of participants, trial conclusion, and journal impact factor. RESULTS: Among 668 trials, the median time to inclusion was 76.1 weeks. Time to inclusion was shorter for trials with industry funding (hazard ratio [HR] 1.39; 95% confidence interval [CI] 1.13-1.71), more participants (HR 1.26; 95% CI 1.17-1.36), and published in higher impact factor journals (HR 1.28; 95% CI 1.14-1.45). The median frequency of inclusion was three. Frequency of inclusion was greater for trials with industry funding (relative risk [RR] 2.36; 95% CI 2.11-2.64), more participants (RR 1.51; 95% CI 1.47-1.55), positive conclusions (RR 1.89; 95% CI 1.68-2.13), and published in higher impact factor journals (RR 1.13; 95% CI 1.08-1.18). CONCLUSION: Certain trial characteristics are associated with faster or more frequent trial inclusion in systematic reviews of type 2 diabetes.

Completion Rate and Reporting of Mandatory Pediatric Postmarketing Studies Under the US Pediatric Research Equity Act.

Importance: Many medicines prescribed to children have not been studied or formally approved for pediatric use. The Pediatric Research Equity Act of 2003 authorized the US Food and Drug Administration (FDA) to require pediatric clinical studies. Objective: To evaluate the characteristics, completion rate, and transparency of study design and results for mandatory pediatric postmarketing studies required under the Pediatric Research Equity Act. Design and Setting: A retrospective cohort study was conducted of pediatric postmarketing studies required for new drugs and new indications approved by the FDA between January 1, 2007, and December 31, 2014, with follow-up through December 1, 2017. Information on the status, design, and results of pediatric studies was obtained from publicly available FDA databases and ClinicalTrials.gov, direct communication with the FDA, and searches of MEDLINE, EMBASE, and Web of Science for peer-reviewed publications. Main Outcomes and Measures: Characteristics and transparency of pediatric studies, results reporting (in ClinicalTrials.gov, peer-reviewed literature, or FDA documents), and availability of pediatric information in drug labels. Rates and times to study completion were evaluated using Cox proportional hazards regression models. Results: Between 2007 and 2014, the FDA approved 114 new drugs and new indications for already approved drugs that were subject to Pediatric Research Equity Act requirements. These drugs were associated with 222 required pediatric postmarketing clinical studies. Overall, 75 pediatric studies (33.8%) were completed as of December 1, 2017. The rates of completion were significantly lower for efficacy studies (38 of 132 [28.8%]) compared with pharmacokinetic studies (19 of 34 [55.9%]; adjusted hazard ratio, 0.31; 95% CI, 0.12-0.82). Information on randomization, blinding, comparator, end point, and study size could not be identified for 74 studies (33.3%), and no reason for discontinuation was provided for 29 of the 42 discontinued studies (69.0%). Among the completed studies, the results were reported for 57 (76.0%). At the time of approval, 18 of 114 drug approvals (15.8%) had any pediatric efficacy, safety, or dosing information in their labels. After a median duration of follow-up of 6.8 years (interquartile range, 4.7-9.1 years), 47 of 114 of drug labels (41.2%) had any pediatric information. Conclusions and Relevance: Only 33.8% of mandatory pediatric postmarketing studies have been completed after a median follow-up of 6.8 years, and most drug labels do not include information important for pediatric use. To improve evidence-based prescribing of medicines to children, more timely completion of pediatric drug studies is needed.

Exclusion of Elderly People from Randomized Clinical Trials of Drugs for Ischemic Heart Disease.

OBJECTIVES: To measure exclusion of elderly adults from randomized trials studying drug interventions for ischemic heart disease (IHD) and describe the characteristics of these trials. DESIGN: Cross-sectional analysis. SETTING: Interventional clinical trials studying a drug intervention for IHD that started in 2006 and after were identified in ClinicalTrials.gov. Data were extracted on study features, including age-based inclusion criteria. Data on participants and their age distribution were collected from trial publications, investigator inquiry, and result data in ClinicalTrials.gov. PARTICIPANTS: Individuals aged 65 and older. MEASUREMENTS: Proportion of trials excluding individuals based on age, mean age of trial participants, and proportion of enrolled participants aged 65 and older and 75 and older. RESULTS: Of 839 identified trials, 446 (53%) explicitly excluded elderly adults. The most-frequent upper age limits were 80 (n = 164) and 75 (n = 114), with a median upper age limit of 80 (interquartile range 75-80). Trials with upper age limit exclusions tended to be smaller (median number of participants 100 vs 201, P < .001) and were more likely to be funded primarily by nonindustry sources (78.3% vs 70.0%, P = .006). The overall mean age of trial participants was 62.7 (mean maximum age 74). The estimated proportion of participants aged 65 and older was 42.5% and the estimated proportion aged 75 and older was 12.3%. CONCLUSION: Despite the high burden of IHD in elderly adults, the majority of drug trials do not enroll participants reflective of age-related prevalence of the disease.