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Concept: Sensitivity analysis

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Background Increasing overuse of opioids in the United States may be driven in part by physician prescribing. However, the extent to which individual physicians vary in opioid prescribing and the implications of that variation for long-term opioid use and adverse outcomes in patients are unknown. Methods We performed a retrospective analysis involving Medicare beneficiaries who had an index emergency department visit in the period from 2008 through 2011 and had not received prescriptions for opioids within 6 months before that visit. After identifying the emergency physicians within a hospital who cared for the patients, we categorized the physicians as being high-intensity or low-intensity opioid prescribers according to relative quartiles of prescribing rates within the same hospital. We compared rates of long-term opioid use, defined as 6 months of days supplied, in the 12 months after a visit to the emergency department among patients treated by high-intensity or low-intensity prescribers, with adjustment for patient characteristics. Results Our sample consisted of 215,678 patients who received treatment from low-intensity prescribers and 161,951 patients who received treatment from high-intensity prescribers. Patient characteristics, including diagnoses in the emergency department, were similar in the two treatment groups. Within individual hospitals, rates of opioid prescribing varied widely between low-intensity and high-intensity prescribers (7.3% vs. 24.1%). Long-term opioid use was significantly higher among patients treated by high-intensity prescribers than among patients treated by low-intensity prescribers (adjusted odds ratio, 1.30; 95% confidence interval, 1.23 to 1.37; P<0.001); these findings were consistent across multiple sensitivity analyses. Conclusions Wide variation in rates of opioid prescribing existed among physicians practicing within the same emergency department, and rates of long-term opioid use were increased among patients who had not previously received opioids and received treatment from high-intensity opioid prescribers. (Funded by the National Institutes of Health.).

Concepts: Patient, Hospital, Retrospective, Physician, Doctor-patient relationship, Odds ratio, Opioid, Sensitivity analysis

194

The ecological impacts of emerging pollutants such as pharmaceuticals are not well understood. The lack of experimental approaches for the identification of pollutant effects in realistic settings (that is, low doses, complex mixtures, and variable environmental conditions) supports the widespread perception that these effects are often unpredictable. To address this, we developed a novel screening method (GSA-QHTS) that couples the computational power of global sensitivity analysis (GSA) with the experimental efficiency of quantitative high-throughput screening (QHTS). We present a case study where GSA-QHTS allowed for the identification of the main pharmaceutical pollutants (and their interactions), driving biological effects of low-dose complex mixtures at the microbial population level. The QHTS experiments involved the integrated analysis of nearly 2700 observations from an array of 180 unique low-dose mixtures, representing the most complex and data-rich experimental mixture effect assessment of main pharmaceutical pollutants to date. An ecological scaling-up experiment confirmed that this subset of pollutants also affects typical freshwater microbial community assemblages. Contrary to our expectations and challenging established scientific opinion, the bioactivity of the mixtures was not predicted by the null mixture models, and the main drivers that were identified by GSA-QHTS were overlooked by the current effect assessment scheme. Our results suggest that current chemical effect assessment methods overlook a substantial number of ecologically dangerous chemical pollutants and introduce a new operational framework for their systematic identification.

Concepts: Scientific method, Biology, Population ecology, Affect, Chemical substance, Experiment, Mixture model, Sensitivity analysis

157

Sensitivity analyses refer to investigations of the degree to which the results of a meta-analysis remain stable when conditions of the data or the analysis change. To the extent that results remain stable, one can refer to them as robust. Sensitivity analyses are rarely conducted in the organizational science literature. Despite conscientiousness being a valued predictor in employment selection, sensitivity analyses have not been conducted with respect to meta-analytic estimates of the correlation (i.e., validity) between conscientiousness and job performance.

Concepts: Scientific method, Mathematical analysis, Logic, Analysis, Sensitivity analysis

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BACKGROUND: Effective psychological therapies have been recommended for common mental health problems, such as depression and anxiety, but provision has been poor. Improving Access to Psychological Therapies (IAPT) may provide a cost-effective solution to this problem. AIMS: To determine the cost-effectiveness of IAPT at the Doncaster demonstration site (2007-2009). METHOD: An economic evaluation comparing costs and health outcomes for patients at the IAPT demonstration site with those for comparator sites, including a separate assessment of lost productivity. Sensitivity analyses were undertaken. RESULTS: The IAPT site had higher service costs and was associated with small additional gains in quality-adjusted life-years (QALYs) compared with its comparator sites, resulting in a cost per QALY gained of £29 500 using the Short Form (SF-6D). Sensitivity analysis using predicted EQ-5D scores lowered this to £16 857. Costs per reliable and clinically significant (RCS) improvement were £9440 per participant. CONCLUSIONS: Improving Access to Psychological Therapies provided a service that was probably cost-effective within the usual National Institute for Health and Clinical Excellence (NICE) threshold range of £20 000-30 000, but there was considerable uncertainty surrounding the costs and outcome differences.

Concepts: Psychology, Health economics, Costs, Cost-utility analysis, Healthcare quality, Sensitivity analysis, Quality-adjusted life year, Cost-Effectiveness Analysis Registry

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BACKGROUND: The advent of endoscopic sphenopalatine artery ligation (ESPAL) for the control of posterior epistaxis provides an effective, low-morbidity treatment option. In the current practice algorithm, ESPAL is pursued after failure of posterior packing. Given the morbidity and limited effectiveness of posterior packing, we sought to determine the cost-effectiveness of first-line ESPAL compared to the current practice model. METHODS: A standard decision analysis model was constructed comparing first-line ESPAL and current practice algorithms. A literature search was performed to determine event probabilities and published Medicare data largely provided cost parameters. The primary outcomes were cost of treatment and resolution of epistaxis. One-way sensitivity analysis was performed for key parameters. RESULTS: Costs for the first-line ESPAL arm and the current practice arm were $6450 and $8246, respectively. One-way sensitivity analyses were performed for key variables including duration of packing. The baseline difference of $1796 in favor of the first-line ESPAL arm was increased to $6263 when the duration of nasal packing was increased from 3 to 5 days. Current practice was favored (cost savings of $437 per patient) if posterior packing duration was decreased from 3 to 2 days. CONCLUSION: This study demonstrates that ESPAL is cost-saving as first-line therapy for posterior epistaxis. Given the improved effectiveness and patient comfort of ESPAL compared to posterior packing, ESPAL should be offered as an initial treatment option for medically stable patients with posterior epistaxis.

Concepts: Costs, Decision theory, Sensitivity analysis, Sphenopalatine artery, Decision analysis, Info-gap decision theory, Epistaxis, Kiesselbach's plexus

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Statistical rate theory calculations, in particular formulations of the chemical master equation, are widely used in order to calculate rate coefficients of interest in combustion environments as a function of temperature and pressure. However despite the increasing accuracy of electronic structure calculations, small uncertainties in the input parameters for these master equation models can lead to relatively large uncertainties in the calculated rate coefficients. Master equation input parameters may be constrained further using experimental data and the relationship between experiment and theory warrants further investigation. In this work the CH3OCH2 + O2 system, of relevance to the combustion of dimethyl ether (DME), is used as an example and the input parameters for master equation calculations on this system are refined through fitting to experimental data. Complementing these fitting calculations, global sensitivity analysis is used to explore which input parameters are constrained by which experimental conditions, and which parameters need to be further constrained in order to accurately predict key elementary rate coefficients. Finally, uncertainties in the calculated rate coefficients are obtained using both correlated and uncorrelated distributions of input parameters.

Concepts: Mathematics, Chemistry, Experiment, Hypothesis, Uncertainty, Experimental uncertainty analysis, Sensitivity analysis, Dimethyl ether

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STUDY QUESTION: Are temporal trends and values of semen quality parameters in France identifiable in partners of totally infertile women? SUMMARY ANSWER: Among a sample of 26 609 partners of totally infertile women undergoing an assisted reproductive technology (ART) procedures in the whole of France over a 17-year period, there was a continuous decrease in semen concentration of about 1.9% per year and a significant decrease in the percentage with morphologically normal forms but no global trend for motility. WHAT IS KNOWN ALREADY: A global decrease in human sperm quality is still debated as geographical differences have been shown, and many criticisms have risen concerning studies with small and biased study populations or inappropriate statistical methodology. However, growing biological, toxicological, experimental and human exposure data support the endocrine disruptors' hypothesis assuming that fetal exposure to endocrine disruptors could impair reproductive outcomes. STUDY DESIGN, SIZE, DURATION: This was a retrospective and descriptive study using data registered by Fivnat, the professional association in charge of statistics for ART in France during the 1989-2005 study period. Data were provided by 126 main ART centres over the whole metropolitan territory. The source population included 154 712 men, aged 18-70, who were partners of couples undergoing their first ART cycle and for whom semen quality indicators (concentration, total motility and percentage of morphologically normal forms), measured on fresh ejaculated semen, were available. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study population was 26 609 partners of women who had both tubes either absent or blocked. The temporal trends for each indicator of semen quality were modelled using a generalized additive model that allowed for nonlinear relationships between variables and were adjusted for season and age. In-depth sensitivity analyses included the reiteration of the analysis on data from a second spermiogram available for each man and on another subsample of men diagnosed as fertile. Variables such as centre, technique (standard in vitro fertilization or intra-cytoplasmic sperm injection) and an interaction factor between technique and time were also included in the model. MAIN RESULTS AND THE ROLE OF CHANCE: There was a significant and continuous decrease in sperm concentration of 32.2% [26.3-36.3] during the study period. Projections indicate that concentration for a 35-year-old man went from an average of 73.6 million/ml [69.0-78.4] in 1989 to 49.9 million/ml [43.5-54.7] in 2005. A significant, but not quantifiable, decrease in the percentage of sperm with morphologically normal forms along the 17-year period was also observed. There was no global trend but a slight, significant increase in total motility between 1994 and 1998 was observed. The results were robust after sensitivity analysis. LIMITATIONS, REASONS FOR CAUTION: Socioeconomic status could not be controlled for. Despite universal access to medical services in France, couples undergoing ART are expected to have a higher educational level on average compared with those of the general population. Therefore, the real values in the general population could be slightly lower than those presented and the decrease possibly stronger, as the population study is less likely to smoke or be overweight, two factors known to impair semen quality. WIDER IMPLICATIONS OF THE FINDINGS: As the men were selected without a priori knowledge regarding their semen quality characteristics, the results are expected to be close to the values in the general French population. The very large sample size and the robustness of the results confer great statistical power and credibility to the results. To our knowledge, it is the first study concluding a severe and general decrease in sperm concentration and morphology at the scale of a whole country over a substantial period. This constitutes a serious public health warning. The link with the environment particularly needs to be determined. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was sought for this study. The authors have no conflict of interest to declare.The study has been authorized by the Commission Nationale de l'Informatique et des Libertés (CNIL), the national authority for the protection of personal data collected on individuals (authorization no DE-2010-063 dated 08/09/2010).

Concepts: Sample size, Sperm, Infertility, Fertility, Spermatozoon, Semen, A priori and a posteriori, Sensitivity analysis

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IMPORTANCE Statin use may be associated with increased musculoskeletal adverse events, especially in physically active individuals. OBJECTIVE To determine whether statin use is associated with musculoskeletal conditions, including arthropathy and injury, in a military health care system. DESIGN A retrospective cohort study with propensity score matching. SETTING San Antonio Military Multi-Market. PARTICIPANTS Tricare Prime/Plus beneficiaries evaluated from October 1, 2003, to March 1, 2010. INTERVENTIONS Statin use during fiscal year 2005. On the basis of medication fills, patients were divided into 2 groups: statin users (received a statin for at least 90 days) and nonusers (never received a statin throughout the study period). MAIN OUTCOMES AND MEASURES Using patients' baseline characteristics, we generated a propensity score that was used to match statin users and nonusers; odds ratios (ORs) were determined for each outcome measure. Secondary analyses determined adjusted ORs for all patients who met study criteria and a subgroup of patients with no comorbidities identified using the Charlson Comorbidity Index. Sensitivity analysis further determined adjusted ORs for a subgroup of patients with no musculoskeletal diseases at baseline and a subgroup of patients who continued statin therapy for 2 years or more. The occurrence of musculoskeletal conditions was determined using prespecified groups of International Classification of Diseases, Ninth Revision, ClinicalModification codes: Msk1, all musculoskeletal diseases; Msk1a, arthropathies and related diseases; Msk1b, injury-related diseases (dislocation, sprain, strain); and Msk2, drug-associated musculoskeletal pain. RESULTS A total of 46 249 individuals met study criteria (13 626 statin users and 32 623 nonusers). Of these, we propensity score-matched 6967 statin users with 6967 nonusers. Among matched pairs, statin users had a higher OR for Msk1 (OR, 1.19; 95% CI, 1.08-1.30), Msk1b (1.13; 1.05-1.21), and Msk2 (1.09; 1.02-1.18); the OR for Msk1a was 1.07 (0.99-1.16; P = .07). Secondary and sensitivity analyses revealed higher adjusted ORs for statin users in all outcome groups. CONCLUSIONS AND RELEVANCE Musculoskeletal conditions, arthropathies, injuries, and pain are more common among statin users than among similar nonusers. The full spectrum of statins' musculoskeletal adverse events may not be fully explored, and further studies are warranted, especially in physically active individuals.

Concepts: Cohort study, Epidemiology, Statin, Propensity score, Comorbidity, Rhabdomyolysis, Sensitivity analysis, Military Health System

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We conducted this systematic review and meta-analysis of prospective studies to determine the effect of probiotic administration on serum C-reactive protein (CRP) concentrations. We searched PubMed-Medline, Web of Science, the Cochrane, and Google Scholar databases (until May 2016) to identify prospective studies evaluating the impact of probiotic administration on CRP. We used a random effects models and generic inverse variance methods to synthesize quantitative data, followed by a leave-one-out method for sensitivity analysis. The systematic review registration number was: CRD42016039457. From a total of 425 entries identified via searches, 20 studies were included in the final analysis. The meta-analysis indicated a significant reduction in serum CRP following probiotic administration with a weighted mean difference (WMD) of -1.35 mg/L, (95% confidence interval (CI) -2.15 to -0.55, I² 65.1%). The WMDs for interleukin 10 (IL10) was -1.65 pg/dL, (95% CI -3.45 to 0.14, I² 3.1%), and -0.45 pg/mL, (95% CI -1.38 to 0.48, I² 10.2%) for tumor necrosis factor alpha (TNF-α). These findings were robust in sensitivity analyses. This meta-analysis suggests that probiotic administration may significantly reduce serum CRP while having no significant effect on serum IL10 and TNF-α.

Concepts: Inflammation, Evidence-based medicine, Randomized controlled trial, Mathematical analysis, Effect size, C-reactive protein, Tumor necrosis factor-alpha, Sensitivity analysis

5

Smoking is strongly associated with schizophrenia. Although it has been widely assumed that this reflects self-medication, recent studies suggest that smoking may be a risk factor for schizophrenia. We performed two-sample bi-directional Mendelian randomization using summary level genomewide association data from the Tobacco And Genetics Consortium and Psychiatric Genomics Consortium. Variants associated with smoking initiation and schizophrenia were combined using an inverse-variance weighted fixed-effects approach. We found evidence consistent with a causal effect of smoking initiation on schizophrenia risk (OR 1.73, 95% CI 1.30-2.25, p < 0.001). However, after relaxing the p-value threshold to include variants from more than one gene and minimize the potential impact of pleiotropy, the association was attenuated (OR 1.03, 95% CI 0.97-1.09, p = 0.32). There was little evidence in support of a causal effect of schizophrenia on smoking initiation (OR 1.01, 95% CI 0.98-1.04, p = 0.32). MR Egger regression sensitivity analysis indicated no evidence for pleiotropy in the effect of schizophrenia on smoking initiation (intercept OR 1.01, 95% CI 0.99-1.02, p = 0.49). Our findings provide little evidence of a causal association between smoking initiation and schizophrenia, in either direction. However, we cannot rule out a causal effect of smoking on schizophrenia related to heavier, lifetime exposure, rather than initiation.

Concepts: Gene, Genetics, Epidemiology, Causality, Nicotine, The Association, Rubin Causal Model, Sensitivity analysis