Morten W. Fagerland

Does physical activity attenuate, or even eliminate, the detrimental association of sitting time with mortality? A harmonised meta-analysis of data from more than 1 million men and women

BACKGROUND High amounts of sedentary behaviour have been associated with increased risks of several chronic conditions and mortality. However, it is unclear whether physical activity attenuates or even eliminates the detrimental effects of prolonged sitting. We examined the associations of sedentary behaviour and physical activity with all-cause mortality. METHODS We did a systematic review, searching six databases (PubMed, PsycINFO, Embase, Web of Science, Sport Discus, and Scopus) from database inception until October, 2015, for prospective cohort studies that had individual level exposure and outcome data, provided data on both daily sitting or TV-viewing time and physical activity, and reported effect estimates for all-cause mortality, cardiovascular disease mortality, or breast, colon, and colorectal cancer mortality. We included data from 16 studies, of which 14 were identified through a systematic review and two were additional unpublished studies where pertinent data were available. All study data were analysed according to a harmonised protocol, which categorised reported daily sitting time and TV-viewing time into four standardised groups each, and physical activity into quartiles (in metabolic equivalent of task [MET]-hours per week). We then combined data across all studies to analyse the association of daily sitting time and physical activity with all-cause mortality, and estimated summary hazard ratios using Cox regression. We repeated these analyses using TV-viewing time instead of daily sitting time. FINDINGS Of the 16 studies included in the meta-analysis, 13 studies provided data on sitting time and all-cause mortality. These studies included 1 005 791 individuals who were followed up for 2-18·1 years, during which 84 609 (8·4%) died. Compared with the referent group (ie, those sitting <4 h/day and in the most active quartile [>35·5 MET-h per week]), mortality rates during follow-up were 12-59% higher in the two lowest quartiles of physical activity (from HR=1·12, 95% CI 1·08-1·16, for the second lowest quartile of physical activity [<16 MET-h per week] and sitting <4 h/day; to HR=1·59, 1·52-1·66, for the lowest quartile of physical activity [<2·5 MET-h per week] and sitting >8 h/day). Daily sitting time was not associated with increased all-cause mortality in those in the most active quartile of physical activity. Compared with the referent (<4 h of sitting per day and highest quartile of physical activity [>35·5 MET-h per week]), there was no increased risk of mortality during follow-up in those who sat for more than 8 h/day but who also reported >35·5 MET-h per week of activity (HR=1·04; 95% CI 0·99-1·10). By contrast, those who sat the least (<4 h/day) and were in the lowest activity quartile (<2·5 MET-h per week) had a significantly increased risk of dying during follow-up (HR=1·27, 95% CI 1·22-1·31). Six studies had data on TV-viewing time (N=465 450; 43 740 deaths). Watching TV for 3 h or more per day was associated with increased mortality regardless of physical activity, except in the most active quartile, where mortality was significantly increased only in people who watched TV for 5 h/day or more (HR=1·16, 1·05-1·28). INTERPRETATION High levels of moderate intensity physical activity (ie, about 60-75 min per day) seem to eliminate the increased risk of death associated with high sitting time. However, this high activity level attenuates, but does not eliminate the increased risk associated with high TV-viewing time. These results provide further evidence on the benefits of physical activity, particularly in societies where increasing numbers of people have to sit for long hours for work and may also inform future public health recommendations. FUNDING None.

Recommended tests for association in 2×2 tables

The asymptotic Pearsons chi-squared test and Fishers exact test have long been the most used for testing association in 2x2 tables. Unconditional tests preserve the significance level and generally are more powerful than Fishers exact test for moderate to small samples, but previously were disadvantaged by being computationally demanding. This disadvantage is now moot, as software to facilitate unconditional tests has been available for years. Moreover, Fishers exact test with mid-p adjustment gives about the same results as an unconditional test. Consequently, several better tests are available, and the choice of a test should depend only on its merits for the application involved. Unconditional tests and the mid-p approach ought to be used more than they now are. The traditional Fishers exact test should practically never be used.

Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol

Abstract Aims Contemporary adjuvant treatment for early breast cancer is associated with improved survival but at the cost of increased risk of cardiotoxicity and cardiac dysfunction. We tested the hypothesis that concomitant therapy with the angiotensin receptor blocker candesartan or the β-blocker metoprolol will alleviate the decline in left ventricular ejection fraction (LVEF) associated with adjuvant, anthracycline-containing regimens with or without trastuzumab and radiation. Methods and results In a 2 × 2 factorial, randomized, placebo-controlled, double-blind trial, we assigned 130 adult women with early breast cancer and no serious co-morbidity to the angiotensin receptor blocker candesartan cilexetil, the β-blocker metoprolol succinate, or matching placebos in parallel with adjuvant anticancer therapy. The primary outcome measure was change in LVEF by cardiac magnetic resonance imaging. A priori, a change of 5 percentage points was considered clinically important. There was no interaction between candesartan and metoprolol treatments (P = 0.530). The overall decline in LVEF was 2.6 (95% CI 1.5, 3.8) percentage points in the placebo group and 0.8 (95% CI −0.4, 1.9) in the candesartan group in the intention-to-treat analysis (P-value for between-group difference: 0.026). No effect of metoprolol on the overall decline in LVEF was observed. Conclusion In patients treated for early breast cancer with adjuvant anthracycline-containing regimens with or without trastuzumab and radiation, concomitant treatment with candesartan provides protection against early decline in global left ventricular function.

The Wilcoxon-Mann-Whitney test under scrutiny.

The Wilcoxon-Mann-Whitney (WMW) test is often used to compare the means or medians of two independent, possibly nonnormal distributions. For this problem, the true significance level of the large sample approximate version of the WMW test is known to be sensitive to differences in the shapes of the distributions. Based on a wide ranging simulation study, our paper shows that the problem of lack of robustness of this test is more serious than is thought to be the case. In particular, small differences in variances and moderate degrees of skewness can produce large deviations from the nominal type I error rate. This is further exacerbated when the two distributions have different degrees of skewness. Other rank-based methods like the Fligner-Policello (FP) test and the Brunner-Munzel (BM) test perform similarly, although the BM test is generally better. By considering the WMW test as a two-sample T test on ranks, we explain the results by noting some undesirable properties of the rank transformation. In practice, the ranked samples should be examined and found to sufficiently satisfy reasonable symmetry and variance homogeneity before the test results are interpreted.

Association between use of β-blockers and prostate cancer-specific survival: A cohort study of 3561 prostate cancer patients with high-risk or metastatic disease

BACKGROUND We recently reported reduced prostate cancer (PCa)-specific mortality for β-blocker users among patients receiving androgen-deprivation therapy in a health survey cohort including 655 PCa patients. Information on clinical characteristics was limited. OBJECTIVE To assess the association between β-blockers and PCa-specific mortality in a cohort of 3561 prostate cancer patients with high-risk or metastatic disease, and to address potential confounding from the use of statins or acetylsalicylic acid (ASA). DESIGN, SETTING, AND PARTICIPANTS Clinical information from all men reported to the Cancer Registry of Norway with a PCa diagnosis between 2004 and 2009 (n=24 571) was coupled with information on filled prescriptions between 2004 and 2011 from the Norwegian Prescription Database. Exclusion criteria were low- or intermediate-risk disease; planned radiotherapy or radical prostatectomy; initiation of β-blocker, ASA, or statin use after diagnosis where applicable; missing information on baseline Gleason score, prostate-specific antigen level, T stage or performance status; and missing follow-up. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Cox proportional hazards modelling and competing risk regression modelling were used to analyse the effects of β-blocker use on all-cause and PCa-specific mortality, respectively. Differences between β-blocker users and nonusers regarding baseline clinical characteristics were assessed by the Wilcoxon-Mann-Whitney U test, Pearson chi-square test, and Student t test. RESULTS AND LIMITATIONS Median follow-up was 39 mo. β-Blocker use was associated with reduced PCa mortality (adjusted subhazard ratio: 0.79; 95% confidence interval [CI], 0.68-0.91; p value: 0.001). The observed reduction in PCa mortality was independent of the use of statins or ASA. We observed no association with all-cause mortality (adjusted hazard ratio: 0.92; 95% CI, 0.83-1.02). The main limitations of the study were the observational study design and short follow-up. CONCLUSIONS β-Blocker use was associated with reduced PCa-specific mortality in patients with high-risk or metastatic disease at the time of diagnosis. Our findings need validation from further observational studies.

Five-Year Outcomes After Laparoscopic Gastric Bypass and Laparoscopic Duodenal Switch in Patients With Body Mass Index of 50 to 60: A Randomized Clinical Trial

IMPORTANCE There is no consensus as to which bariatric procedure is preferred to reduce weight and improve health in patients with a body mass index higher than 50. OBJECTIVE To compare 5-year outcomes after Roux-en-Y gastric bypass (gastric bypass) and biliopancreatic diversion with duodenal switch (duodenal switch). DESIGN, SETTING, AND PARTICIPANTS Randomized clinical open-label trial at Oslo University Hospital, Oslo, Norway, and Sahlgrenska University Hospital, Gothenburg, Sweden. Participants were recruited between March 17, 2006, and August 20, 2007, and included 60 patients aged 20 to 50 years with a body mass index of 50 to 60. The current study provides the 5-year follow-up analyses by intent to treat, excluding one participant accepted for inclusion who declined being operated on prior to knowing to what group he was randomized. INTERVENTIONS Laparoscopic gastric bypass and laparoscopic duodenal switch. MAIN OUTCOMES AND MEASURES Body mass index and secondary outcomes including anthropometric measures, cardiometabolic risk factors, pulmonary function, vitamin status, gastrointestinal symptoms, health-related quality of life, and adverse events. RESULTS Sixty patients were randomly assigned and operated on with gastric bypass (n = 31) and duodenal switch (n = 29). Fifty-five patients (92%) completed the study. Five years after surgery, the mean reductions in body mass index were 13.6 (95% CI, 11.0-16.1) and 22.1 (95% CI, 19.5-24.7) after gastric bypass and duodenal switch, respectively. The mean between-group difference was 8.5 (95% CI, 4.9-12.2; P < .001). Remission rates of type 2 diabetes mellitus and metabolic syndrome and changes in blood pressure and lung function were similar between groups. Reductions in total cholesterol, low-density lipoprotein cholesterol, triglycerides, and fasting glucose were significantly greater after duodenal switch compared with gastric bypass. Serum concentrations of vitamin A and 25-hydroxyvitamin D were significantly reduced after duodenal switch compared with gastric bypass. Duodenal switch was associated with more gastrointestinal adverse effects. Health-related quality of life was similar between groups. Patients with duodenal switch underwent more surgical procedures related to the initial procedure (13 [44.8%] vs 3 [9.7%] patients; P = .002) and had significantly more hospital admissions compared with patients with gastric bypass. CONCLUSIONS AND RELEVANCE In patients with a body mass index of 50 to 60, duodenal switch resulted in greater weight loss and greater improvements in low-density lipoprotein cholesterol, triglyceride, and glucose levels 5 years after surgery compared with gastric bypass while improvements in health-related quality of life were similar. However, duodenal switch was associated with more surgical, nutritional, and gastrointestinal adverse effects. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00327912.

Use of β-blockers is associated with prostate cancer-specific survival in prostate cancer patients on androgen deprivation therapy.

Experimental evidence suggests a role for the β2‐adrenergic receptor pathway in prostate cancer (PCa). We have investigated the association of β‐blocker use with PCa incidence and survival in a Norwegian cohort.

Performance of five two-sample location tests for skewed distributions with unequal variances.

Tests for comparing the locations of two independent populations are associated with different null hypotheses, but results are often interpreted as evidence for or against equality of means or medians. We examine the appropriateness of this practice by investigating the performance of five frequently used tests: the two-sample T test, the Welch U test, the Yuen-Welch test, the Wilcoxon-Mann-Whitney test, and the Brunner-Munzel test. Under combined violations of normality and variance homogeneity, the true significance level and power of the tests depend on a complex interplay of several factors. In a wide ranging simulation study, we consider scenarios differing in skewness, skewness heterogeneity, variance heterogeneity, sample size, and sample size ratio. We find that small differences in distribution properties can alter test performance markedly, thus confounding the effort to present simple test recommendations. Instead, we provide detailed recommendations in Appendix A. The Welch U test is recommended most frequently, but cannot be considered an omnibus test for this problem.

t-tests, non-parametric tests, and large studies—a paradox of statistical practice?

BackgroundDuring the last 30 years, the median sample size of research studies published in high-impact medical journals has increased manyfold, while the use of non-parametric tests has increased at the expense of t-tests. This paper explores this paradoxical practice and illustrates its consequences.MethodsA simulation study is used to compare the rejection rates of the Wilcoxon-Mann-Whitney (WMW) test and the two-sample t-test for increasing sample size. Samples are drawn from skewed distributions with equal means and medians but with a small difference in spread. A hypothetical case study is used for illustration and motivation.ResultsThe WMW test produces, on average, smaller p-values than the t-test. This discrepancy increases with increasing sample size, skewness, and difference in spread. For heavily skewed data, the proportion of p<0.05 with the WMW test can be greater than 90% if the standard deviations differ by 10% and the number of observations is 1000 in each group. The high rejection rates of the WMW test should be interpreted as the power to detect that the probability that a random sample from one of the distributions is less than a random sample from the other distribution is greater than 50%.ConclusionsNon-parametric tests are most useful for small studies. Using non-parametric tests in large studies may provide answers to the wrong question, thus confusing readers. For studies with a large sample size, t-tests and their corresponding confidence intervals can and should be used even for heavily skewed data.

The McNemar test for binary matched-pairs data: mid-p and asymptotic are better than exact conditional

BackgroundStatistical methods that use the mid-p approach are useful tools to analyze categorical data, particularly for small and moderate sample sizes. Mid-p tests strike a balance between overly conservative exact methods and asymptotic methods that frequently violate the nominal level. Here, we examine a mid-p version of the McNemar exact conditional test for the analysis of paired binomial proportions.MethodsWe compare the type I error rates and power of the mid-p test with those of the asymptotic McNemar test (with and without continuity correction), the McNemar exact conditional test, and an exact unconditional test using complete enumeration. We show how the mid-p test can be calculated using eight standard software packages, including Excel.ResultsThe mid-p test performs well compared with the asymptotic, asymptotic with continuity correction, and exact conditional tests, and almost as good as the vastly more complex exact unconditional test. Even though the mid-p test does not guarantee preservation of the significance level, it did not violate the nominal level in any of the 9595 scenarios considered in this article. It was almost as powerful as the asymptotic test. The exact conditional test and the asymptotic test with continuity correction did not perform well for any of the considered scenarios.ConclusionsThe easy-to-calculate mid-p test is an excellent alternative to the complex exact unconditional test. Both can be recommended for use in any situation. We also recommend the asymptotic test if small but frequent violations of the nominal level is acceptable.