Comparison among random forest, logistic regression, and existing clinical risk scores for predicting outcomes in patients with atrial fibrillation: A report from the J-RHYTHM registry

BACKGROUND: Machine learning (ML) has emerged as a promising tool for risk stratification. However, few studies have applied ML to risk assessment of patients with atrial fibrillation (AF). HYPOTHESIS: We aimed to compare the performance of random forest (RF), logistic regression (LR), and conventional risk schemes in predicting the outcomes of AF. METHODS: We analyzed data from 7406 nonvalvular AF patients (median age 71 years, female 29.2%) enrolled in a nationwide AF registry (J‐RHYTHM Registry) and who were followed for 2 years. The endpoints were thromboembolisms, major bleeding, and all‐cause mortality. Models were generated from potential predictors using an RF model, stepwise LR model, and the thromboembolism (CHADS(2) and CHA(2)DS(2)‐VASc) and major bleeding (HAS‐BLED, ORBIT, and ATRIA) scores. RESULTS: For thromboembolisms, the C‐statistic of the RF model was significantly higher than that of the LR model (0.66 vs. 0.59, p = .03) or CHA(2)DS(2)‐VASc score (0.61, p < .01). For major bleeding, the C‐statistic of RF was comparable to the LR (0.69 vs. 0.66, p = .07) and outperformed the HAS‐BLED (0.61, p < .01) and ATRIA (0.62, p < .01) but not the ORBIT (0.67, p = .07). The C‐statistic of RF for all‐cause mortality was comparable to the LR (0.78 vs. 0.79, p = .21). The calibration plot for the RF model was more aligned with the observed events for major bleeding and all‐cause mortality. CONCLUSIONS: The RF model performed as well as or better than the LR model or existing clinical risk scores for predicting clinical outcomes of AF

The Long-Term Effects of a Kampo Medicine, Juzentaihoto, on Maintenance of Antibody Titer in Elderly People after Influenza Vaccination

We have performed a broad-ranging analysis of the adjuvant effect of a Kampo medicine, juzentaihoto (JTT), on influenza vaccination in a multicenter randomized controlled trial. In this study, the enhancing effect of JTT on antibody titer after influenza vaccination was studied for 28 weeks in elderly people who were in the high-risk group for influenza infection. In total, 91 subjects over 65 years old were recruited from four long-term-care facilities located in Chiba, Gunma, and Toyama prefectures in Japan. Participants were randomly assigned to the JTT and the control groups. Blood samples were taken at 4 weeks before vaccination, at the time of vaccination, and then at 4, 8, 12, and 24 weeks after vaccination. The hemagglutination inhibition (HI) titers against A/California/7/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 were then manually measured. A significant increase in HI titer against H3N2 was observed at week 8 after vaccination in the JTT group compared with the control group (P=0.0229), and the HI titer of the JTT group significantly increased from 4 to 24 weeks (P=0.0468), compared with the control group. In conclusion, our results indicated that JTT increased and prolonged antibody production against A/Victoria/210/2009 (H3N2), in particular, after influenza vaccination

Genetic Study in Left Ventricular Noncompaction

Background—Left ventricular noncompaction (LVNC) has since been classified as a primary genetic cardiomyopathy, but the genetic basis is not fully evaluated. The aim of the present study was to identify the genetic spectrum using next-generation sequencing and to evaluate genotype–phenotype correlations in LVNC patients. Methods and Results—Using next-generation sequencing, we targeted and sequenced 73 genes related to cardiomyopathy in 102 unrelated LVNC patients. We identified 43 pathogenic variants in 16 genes in 39 patients (38%); 28 were novel variants. Sarcomere gene variants accounted for 63%, and variants in genes associated with channelopathies accounted for 12%. MYH7 and TAZ pathogenic variants were the most common, and rare variant collapsing analysis showed variants in these genes contributed to the risk of LVNC, although patients carrying MYH7 and TAZ pathogenic variants displayed different phenotypes. Patients with pathogenic variants had early age of onset and more severely decreased left ventricular ejection fractions. Survival analysis showed poorer prognosis in patients with pathogenic variants, especially those with multiple variants: All died before their first birthdays. Adverse events were noted in 17 patients, including 13 deaths, 3 heart transplants, and 1 implantable cardioverter-defibrillator insertion. Congestive heart failure at diagnosis and pathogenic variants were independent risk factors for these adverse events. Conclusions—Next-generation sequencing revealed a wide spectrum of genetic variations and a high incidence of pathogenic variants in LVNC patients. These pathogenic variants were independent risk factors for adverse events. Patients harboring pathogenic variants showed poor prognosis and should be followed closely

Gemcitabine and vinorelbine followed by docetaxel in patients with advanced non-small-cell lung cancer: a multi-institutional phase II trial of nonplatinum sequential triplet combination chemotherapy (JMTO LC00-02)

To evaluate the efficacy and toxicity of the sequential nonplatinum combination chemotherapy consisting of gemcitabine (GEM) and vinorelbine (VNR) followed by docetaxel (DOC) in patients with advanced non-small-cell lung cancer (NSCLC), we conducted the multiinstitutional phase II study. A total of 44 chemotherapy-naive patients with advanced NSCLC were treated with GEM 1000 mg m−2 and VNR 25 mg m−2 intravenously on days 1 and 8 every 3 weeks for three cycles. DOC 60 mg m−2 was then administrated intravenously at 3-week intervals for three cycles. Patients were evaluated for response and toxicity with each cycle of the treatment. The major objective response rate was 47.7% (95% confidence interval (CI), 33.8–62.1%). Median survival time (MST) was 15.7 months and 1-year survival rate was 59%. In the GEM/VNR cycle, grade 3/4 neutropenia occurred in 36.3%, grade 3/4 anaemia in two patients (4.5%) and grade 3 thrombocytopenia in one patient (2.3%). Grade 3 pneumonitis occurred in two patients (4.5%) in GEM/VNR cycles. In the DOC cycles, grade 3/4 neutropenia occurred in 39.4% but no patient experienced grade 3/4 anaemia or thrombocytopenia. Of the 44 eligible patients, 33 patients completed three cycles of GEM/VNR and 22 patients completed six cycles of planned chemotherapy (three cycles of GEM/VNR followed by three cycles of DOC). The sequential triplet nonplatinum chemotherapy consisted of GEM/VNR followed by DOC, and was very active and well tolerated. This study forms the basis for an ongoing phase III trial that compares this nonplatinum triplet and standard platinum doublet combination (carboplatin/paclitaxel)

Polyunsaturated fatty acids for the primary and secondary prevention of cardiovascular disease

Background: Evidence on the health effects of total polyunsaturated fatty acids (PUFA) is equivocal. Fish oils are rich in omega-3 PUFA and plant oils in omega-6 PUFA. Evidence suggests increasing PUFA-rich foods, supplements or supplemented foods can reduce serum cholesterol, but may increase body weight, so overall cardiovascular effects are unclear. Objectives: To assess effects of increasing PUFA intake on cardiovascular disease (CVD) and all-cause mortality in adults. Search method: We searched CENTRAL, MEDLINE and Embase to April 2017 and ClinicalTrials.com and World Health Organization International Clinical Trials Registry Platform to September 2016, without language restrictions. We checked trials included in relevant systematic reviews. Selection criteria: We included randomised controlled trials (RCTs) comparing higher with lower PUFA intakes in adults with or without CVD that assessed effects over ≥12 months. We included full-text, abstracts, trials registry entries and unpublished data. Outcomes were all-cause mortality, CVD mortality and events, risk factors (blood lipids, adiposity, blood pressure), and adverse events. We excluded trials where we could not separate effects of PUFA intake from other dietary, lifestyle or medication interventions. Data collection and analysis: Two authors independently screened titles/abstracts, assessed trials for inclusion, extracted data, and assessed risk of bias. We wrote to authors of included studies for further data. Meta-analyses used random-effects analysis, sensitivity analyses included fixed-effects and limiting to low summary risk of bias. We assessed GRADE quality of evidence. Main result: We included 49 RCTs randomising 24,272 participants, with duration of one to eight years. Twelve included trials were at low summary risk of bias, 33 recruited participants without cardiovascular disease. Baseline PUFA intake was unclear in most trials, but 3.9% to 8% of total energy intake where reported. Most trials gave supplemental capsules, but eight gave dietary advice, eight gave supplemental foods such as nuts or margarine, and three used a combination of methods to increase PUFA. Increasing PUFA intake probably has little or no effect on all-cause mortality (risk 3.4% vs 3.3% in primary prevention, 11.7% vs 11.5% in secondary prevention, risk ratio (RR) 0.98, 95% confidence interval (CI) 0.89 to 1.07, 24 trials in 19290 participants), but probably reduces risk of CVD events from 5.8% to 4.9% in primary prevention, 23.3% to 20.8% in secondary prevention (RR 0.89, 95% CI 0.79 to 1.01, 20 trials in 17,073 participants), both moderate quality evidence. Increasing PUFA may reduce risk of CHD events from 13.4% to 7.1% primary prevention, 14.3% to 13.7% secondary prevention (RR 0.87, 95% CI 0.72 to 1.06, 15 trials, 10,076 participants), CHD death (5.2% to 4.4% primary prevention, 6.8% to 6.1% secondary prevention, RR 0.91, 95% CI 0.78 to 1.06, 9 trials, 8810 participants) and may slightly reduce stroke risk (2.1% to 1.5% primary prevention, RR 0.91, 95% CI 0.58 to 1.44, 11 trials, 14,742 participants), but has little or no effect on cardiovascular mortality (RR 1.02, 95% CI 0.82 to 1.26, I2 31%, 16 trials, 15,107 participants) all low quality evidence. Effects of increasing PUFA on major adverse cardiac and cerebrovascular events and atrial fibrillation are unclear as evidence is of very low quality. Event outcomes were all downgraded for indirectness, as most events occurred in men in westernised countries. Increasing PUFA intake reduces total cholesterol (MD -0.12 mmol/L, 95% CI -0.23 to -0.02, I2 79%, 8072 participants, 26 trials) and probably decreases triglycerides (TG, MD -0.12 mmol/L, 95% CI -0.20 to -0.04, I2 50%, 3905 participants, 20 trials), but has little or no effect on HDL (MD -0.01 mmol/L, 95% CI -0.02 to 0.01, I2 0%, 4674 participants, 18 trials) and LDL (MD -0.01 mmol/L, 95% CI -0.09 to 0.06, I2 44%, 3362 participants, 15 trials). Increasing PUFA probably causes slight weight gain (MD 0.76 kg, 95% CI 0.34 to 1.19, I2 59%, 7100 participants, 12 trials). Effects of increasing PUFA on serious adverse events such as pulmonary embolism and bleeding are unclear as the evidence is of very low quality. Authors' conclusions: Increasing PUFA intake probably reduces risk of CVD events, may reduce risk of CHD events and CHD mortality,and may slightly reduce stroke risk, but has little or no effect on all-cause or CVD mortality. The mechanism may be via lipid reduction, but increasing PUFA probably slightly increases weight

Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease

Background: Researchers have suggested that omega-3 polyunsaturated fatty acids from oily fish (long-chain omega-3 (LCn3), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), as well as from plants (alpha-linolenic acid (ALA)) benefit cardiovascular health. Guidelines recommend increasing omega-3-rich foods, and sometimes supplementation, but recent trials have not confirmed this. Objectives: To assess effects of increased intake of fish- and plant-based omega-3 for all-cause mortality, cardiovascular (CVD) events, adiposity and lipids. Search methods: We searched CENTRAL, MEDLINE and Embase to April 2017, plus ClinicalTrials.gov and World Health Organization International Clinical Trials Registry to September 2016, with no language restrictions. We handsearched systematic review references and bibliographies and contacted authors. Selection criteria: We included randomised controlled trials (RCTs) that lasted at least 12 months and compared supplementation and/or advice to increase LCn3 or ALA intake versus usual or lower intake. Data collection and analysis: Two review authors independently assessed studies for inclusion, extracted data and assessed validity. We performed separate random-effects meta-analysis for ALA and LCn3 interventions, and assessed dose-response relationships through meta-regression. Main results: We included 79 RCTs (112,059 participants) in this review update and found that 25 were at low summary risk of bias. Trials were of 12 to 72 months' duration and included adults at varying cardiovascular risk, mainly in high-income countries. Most studies assessed LCn3 supplementation with capsules, but some used LCn3- or ALA-rich or enriched foods or dietary advice compared to placebo or usual diet. Meta-analysis and sensitivity analyses suggested little or no effect of increasing LCn3 on all-cause mortality (RR 0.98, 95% CI 0.90 to 1.03, 92,653 participants; 8189 deaths in 39 trials, high-quality evidence), cardiovascular mortality (RR 0.95, 95% CI 0.87 to 1.03, 67,772 participants; 4544 CVD deaths in 25 RCTs), cardiovascular events (RR 0.99, 95% CI 0.94 to 1.04, 90,378 participants; 14,737 people experienced events in 38 trials, high-quality evidence), coronary heart disease (CHD) mortality (RR 0.93, 95% CI 0.79 to 1.09, 73,491 participants; 1596 CHD deaths in 21 RCTs), stroke (RR 1.06, 95% CI 0.96 to 1.16, 89,358 participants; 1822 strokes in 28 trials) or arrhythmia (RR 0.97, 95% CI 0.90 to 1.05, 53,796 participants; 3788 people experienced arrhythmia in 28 RCTs). There was a suggestion that LCn3 reduced CHD events (RR 0.93, 95% CI 0.88 to 0.97, 84,301 participants; 5469 people experienced CHD events in 28 RCTs); however, this was not maintained in sensitivity analyses - LCn3 probably makes little or no difference to CHD event risk. All evidence was of moderate GRADE quality, except as noted. Increasing ALA intake probably makes little or no difference to all-cause mortality (RR 1.01, 95% CI 0.84 to 1.20, 19,327 participants; 459 deaths, 5 RCTs),cardiovascular mortality (RR 0.96, 95% CI 0.74 to 1.25, 18,619 participants; 219 cardiovascular deaths, 4 RCTs), and it may make little or no difference to CHD events (RR 1.00, 95% CI 0.80 to 1.22, 19,061 participants, 397 CHD events, 4 RCTs, low-quality evidence). However, increased ALA may slightly reduce risk of cardiovascular events (from 4.8% to 4.7%, RR 0.95, 95% CI 0.83 to 1.07, 19,327 participants; 884 CVD events, 5 RCTs, low-quality evidence), and probably reduces risk of CHD mortality (1.1% to 1.0%, RR 0.95, 95% CI 0.72 to 1.26, 18,353 participants; 193 CHD deaths, 3 RCTs), and arrhythmia (3.3% to 2.6%, RR 0.79, 95% CI 0.57 to 1.10, 4,837 participants; 141 events, 1 RCT). Effects on stroke are unclear. Sensitivity analysis retaining only trials at low summary risk of bias moved effect sizes towards the null (RR 1.0) for all LCn3 primary outcomes except arrhythmias, but for most ALA outcomes, effect sizes moved to suggest protection. LCn3 funnel plots suggested that adding in missing studies/results would move effect sizes towards null for most primary outcomes. There were no dose or duration effects in subgrouping or meta-regression. There was no evidence that increasing LCn3 or ALA altered serious adverse events, adiposity or lipids, although LCn3 slightly reduced triglycerides and increased HDL. ALA probably reduces HDL (high- or moderate-quality evidence). Authors' conclusions: This is the most extensive systematic assessment of effects of omega-3 fats on cardiovascular health to date. Moderate- and high-quality evidence suggests that increasing EPA and DHA has little or no effect on mortality or cardiovascular health (evidence mainly from supplement trials). Previous suggestions of benefits from EPA and DHA supplements appear to spring from trials with higher risk of bias. Low-quality evidence suggests ALA may slightly reduce CVD event risk, CHD mortality and arrhythmia