Design of cohort studies in chronic diseases using routinely collected databases when a prescription is used as surrogate outcome

BACKGROUND: There has been little research on design of studies based on routinely collected data when the clinical endpoint of interest is not recorded, but can be inferred from a prescription. This often happens when exploring the effect of a drug on chronic diseases. Using the LifeLink claims database in studying the possible anti-inflammatory effects of statins in rheumatoid arthritis (RA), oral steroids (OS) were treated as surrogate of inflammatory flare-ups. We compared two cohort study designs, the first using time to event outcomes and the second using quantitative amount of the surrogate. METHODS: RA patients were extracted from the LifeLink database. In the first study, patients were split into two sub-cohorts based on whether they were using OS within a specified time window of the RA index date (first record of RA). Using Cox models we evaluated the association between time-varying exposure to statins and (i) initiation of OS therapy in the non-users of OS at RA index date and (ii) cessation of OS therapy in the users of OS at RA index date. In the second study, we matched new statin users to non users on age and sex. Zero inflated negative binomial models were used to contrast the number of days' prescriptions of OS in the year following date of statin initiation for the two exposure groups. RESULTS: In the unmatched study, the statin exposure hazard ratio (HR) of initiating OS in the 31451 non-users of OS at RA index date was 0.96(95% CI 0.9,1.1) and the statin exposure HR of cessation of OS therapy in the 6026 users of OS therapy at RA index date was 0.95 (0.87,1.05). In the matched cohort of 6288 RA patients the statin exposure rate ratio for duration on OS therapy was 0.88(0.76,1.02). There was digit preference for outcomes in multiples of 7 and 30 days. CONCLUSIONS: The 'time to event' study design was preferable because it better exploits information on all available patients and provides a degree of robustness toward confounding. We found no convincing evidence that statins reduce inflammation in RA patients

Are genetic risk factors for psychosis also associated with dimension-specific psychotic experiences in adolescence?

Psychosis has been hypothesised to be a continuously distributed quantitative phenotype and disorders such as schizophrenia and bipolar disorder represent its extreme manifestations. Evidence suggests that common genetic variants play an important role in liability to both schizophrenia and bipolar disorder. Here we tested the hypothesis that these common variants would also influence psychotic experiences measured dimensionally in adolescents in the general population. Our aim was to test whether schizophrenia and bipolar disorder polygenic risk scores (PRS), as well as specific single nucleotide polymorphisms (SNPs) previously identified as risk variants for schizophrenia, were associated with adolescent dimension-specific psychotic experiences. Self-reported Paranoia, Hallucinations, Cognitive Disorganisation, Grandiosity, Anhedonia, and Parent-rated Negative Symptoms, as measured by the Specific Psychotic Experiences Questionnaire (SPEQ), were assessed in a community sample of 2,152 16-year-olds. Polygenic risk scores were calculated using estimates of the log of odds ratios from the Psychiatric Genomics Consortium GWAS stage-1 mega-analysis of schizophrenia and bipolar disorder. The polygenic risk analyses yielded no significant associations between schizophrenia and bipolar disorder PRS and the SPEQ measures. The analyses on the 28 individual SNPs previously associated with schizophrenia found that two SNPs in TCF4 returned a significant association with the SPEQ Paranoia dimension, rs17512836 (p-value=2.57x10-4) and rs9960767 (p-value=6.23x10-4). Replication in an independent sample of 16-year-olds (N=3,427) assessed using the Psychotic-Like Symptoms Questionnaire (PLIKS-Q), a composite measure of multiple positive psychotic experiences, failed to yield significant results. Future research with PRS derived from larger samples, as well as larger adolescent validation samples, would improve the predictive power to test these hypotheses further. The challenges of relating adult clinical diagnostic constructs such as schizophrenia to adolescent psychotic experiences at a genetic level are discussed

Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions

Recent genome-wide association studies have reported that, amongst other microglial genes, variants in TREM2 can profoundly increase the incidence of developing Alzheimer's disease (AD). We have investigated the role of TREM2 in primary microglial cultures from wild-type mice by using siRNA to decrease Trem2 expression, and in parallel from knock-in mice heterozygous or homozygous for the Trem2 R47H AD risk variant (from the Jackson laboratories). The prevailing phenotype of Trem2 R47H knock-in mice was decreased expression levels of Trem2 in microglia, which resulted in decreased density of microglia in the hippocampus. Overall, primary microglia with reduced Trem2 expression, either by siRNA or from the R47H knock-in mice, displayed a similar phenotype. Comparison of the effects of decreased Trem2 expression under conditions of LPS pro-inflammatory or IL4 anti-inflammatory stimulation revealed the importance of Trem2 in driving a number of the genes up-regulated in the anti-inflammatory phenotype, whether treated with RNAi or performed with microglia carrying the R47H variant. In particular, Trem2 knockdown decreased levels of the transcription factor STAT6. STAT6 is the key mediator downstream from IL4 and controls expression of genes including Arg1, which also showed decreased IL4-induced expression when Trem2 expression was decreased. LPS-induced pro-inflammatory stimulation suppressed Trem2 expression, thus preventing TREM2's anti-inflammatory drive. The importance of Trem2 activity in regulating the pro- and anti-inflammatory balance of microglia, particularly mediating effects of the IL4-regulated anti-inflammatory pathway, has important implications for fighting neurodegenerative disease

A randomized, placebo-controlled double-blinded comparative clinical study of five over-the-counter non-pharmacological topical analgesics for myofascial pain: single session findings

<p>Abstract</p> <p>Objectives</p> <p>To investigate the effects of topical agents for the treatment of Myofascial Pain Syndrome (MPS) and Myofascial Trigger Point (MTRP).</p> <p>Methods</p> <p>Subjects with an identifiable trigger point in the trapezius muscle, age 18-80 were recruited for a single-session randomized, placebo-blinded clinical study. Baseline measurements of trapezius muscle pressure pain threshold (PPT: by pressure algometer) along with right and left cervical lateral flexion (rangiometer) were obtained by a blinded examiner. An assessor blinded to the outcomes assessments applied one of 6 topical formulations which had been placed in identical plastic containers. Five of these topicals were proposed active formulations; the control group was given a non-active formulation (PLA). Five minutes after the application of the formula the outcome measures were re-tested. Data were analyzed with a 5-way ANOVA and Holms-adjusted t-tests with an alpha level of 0.05.</p> <p>Results</p> <p>120 subjects were entered into the study (63 females; ages 16-82); 20 subjects randomly allocated into each group. The pre- and post-treatment results for pressure threshold did show significant intra-group increases for the Ben-Gay Ultra Strength Muscle Pain Ointment (BG), the Professional Therapy MuscleCare Roll-on (PTMC roll-on) and Motion Medicine Cream (MM) with an increased threshold of 0.5 kg/cm²(+/-0.15), 0.72 kg/cm^{<b>2 </b>}(+/-0.17) and 0.47 Kg/cm^{<b>2 </b>}(+/-0.19) respectively. With respect to the inter-group comparisons, PTMC roll-on showed significant increases in pressure threshold compared with Placebo (PLA) (p = 0.002) and Icy Hot Extra Strength Cream (IH) (p = 0.006). In addition, BG demonstrated significant increases in pressure threshold compared with PLA (p = 0.0003).</p> <p>Conclusions</p> <p>With regards to pressure threshold, PTMC roll-on, BG and MM showed significant increases in pain threshold tolerance after a short-term application on a trigger points located in the trapezius muscle. PTMC roll-on and BG were both shown to be superior vs placebo while PTMC was also shown to be superior to IH in patients with trigger points located in the trapezius muscle on a single application.</p> <p>CMCC Research Ethics Board Approval # 1012X01, 2011</p

Discrepancy between prevalence and perceived effectiveness of treatment methods in myofascial pain syndrome: Results of a cross-sectional, nationwide survey

Background: Myofascial pain is a common dysfunction with a lifetime prevalence affecting up to 85% of the general population. Current guidelines for the management of myofascial pain are not available. In this study we investigated how physicians on the basis of prescription behaviour evaluate the effectiveness of treatment options in their management of myofascial pain. Methods: We conducted a cross-sectional, nationwide survey with a standardized questionnaire among 332 physicians (79.8% male, 25.6% female, 47.5 +/- 9.6 years) experienced in treating patients with myofascial pain. Recruitment of physicians took place at three German meetings of pain therapists, rheumatologists and orthopaedists, respectively. Physicians estimated the prevalence of myofascial pain amongst patients in their practices, stated what treatments they used routinely and then rated the perceived treatment effectiveness on a six-point scale (with 1 being excellent). Data are expressed as mean +/- standard deviation. Results: The estimated overall prevalence of active myofascial trigger points is 46.1 +/- 27.4%. Frequently prescribed treatments are analgesics, mainly metamizol/paracetamol (91.6%), non-steroidal anti-inflammatory drugs/coxibs (87.0%) or weak opioids (81.8%), and physical therapies, mainly manual therapy (81.1%), TENS (72.9%) or acupuncture (60.2%). Overall effectiveness ratings for analgesics (2.9 +/- 0.7) and physical therapies were moderate (2.5 +/- 0.8). Effectiveness ratings of the various treatment options between specialities were widely variant. 54.3% of all physicians characterized the available treatment options as insufficient. Conclusions: Myofascial pain was estimated a prevalent condition. Despite a variety of commonly prescribed treatments, the moderate effectiveness ratings and the frequent characterizations of the available treatments as insufficient suggest an urgent need for clinical research to establish evidence-based guidelines for the treatment of myofascial pain syndrome

Bias in random forest variable importance measures: Illustrations, sources and a solution

BACKGROUND: Variable importance measures for random forests have been receiving increased attention as a means of variable selection in many classification tasks in bioinformatics and related scientific fields, for instance to select a subset of genetic markers relevant for the prediction of a certain disease. We show that random forest variable importance measures are a sensible means for variable selection in many applications, but are not reliable in situations where potential predictor variables vary in their scale of measurement or their number of categories. This is particularly important in genomics and computational biology, where predictors often include variables of different types, for example when predictors include both sequence data and continuous variables such as folding energy, or when amino acid sequence data show different numbers of categories. RESULTS: Simulation studies are presented illustrating that, when random forest variable importance measures are used with data of varying types, the results are misleading because suboptimal predictor variables may be artificially preferred in variable selection. The two mechanisms underlying this deficiency are biased variable selection in the individual classification trees used to build the random forest on one hand, and effects induced by bootstrap sampling with replacement on the other hand. CONCLUSION: We propose to employ an alternative implementation of random forests, that provides unbiased variable selection in the individual classification trees. When this method is applied using subsampling without replacement, the resulting variable importance measures can be used reliably for variable selection even in situations where the potential predictor variables vary in their scale of measurement or their number of categories. The usage of both random forest algorithms and their variable importance measures in the R system for statistical computing is illustrated and documented thoroughly in an application re-analyzing data from a study on RNA editing. Therefore the suggested method can be applied straightforwardly by scientists in bioinformatics research

The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs

BACKGROUND: Recent reports have raised concerns that postnatal steroids may cause neuro-developmental impairment in preterm infants. This systematic review was performed with the objective of determining whether glucocorticoid therapy, to prevent or treat bronchopulmonary dysplasia, impairs neuro-developmental outcomes in preterm infants. METHOD: A systematic review of the literature was performed. Medline was searched and articles retrieved using predefined criteria. Data from randomized controlled trials with adequate neuro-developmental follow up (to at least one year) were entered into a meta-analysis to determine the effects of postnatal treatment of preterm infants with glucocorticoids. Cerebral palsy rates, and neuro-developmental impairment (developmental score more than 2SD below the mean, or cerebral palsy or blindness) were analyzed. The studies were divided into 2 groups according to the extent of contamination of the results by treatment of controls with steroids after the initial study period, those with less than 30% contamination, and those with more than 30% contamination or size of contamination not reported. RESULTS: Postnatal steroid therapy is associated with an increase in cerebral palsy and neuro-developmental impairment. The studies with less contamination show a greater effect of the steroids, consistent with a real direct toxic effect of steroids on the developing central nervous system. The typical relative risk for the development of cerebral palsy derived from studies with less than 30% contamination is 2.86 (95% CI 1.95, 4.19). The typical relative risk for the development of neuro-developmental disability among followed up infants from studies with less than 30% contamination is 1.66 (95% CI 1.26, 2.19). From this subgroup of studies, the number of premature infants who need to be treated to have one more infant with cerebral palsy (number needed to harm, NNH) is 7; to have one more infant with neuro-developmental impairment the NNH is 11. CONCLUSIONS: Postnatal pharmacologic steroid treatment for prevention or treatment of bronchopulmonary dysplasia is associated with dramatic increases in neuro-developmental impairment. As there is no clear evidence in the literature of long term benefit, their use for this indication should be abandoned

The association between iliocostal distance and the number of vertebral and non-vertebral fractures in women and men registered in the Canadian Database For Osteoporosis and Osteopenia (CANDOO)

BACKGROUND: The identification of new methods of evaluating patients with osteoporotic fracture should focus on their usefulness in clinical situations such that they are easily measured and applicable to all patients. Thus, the purpose of this study was to examine the association between iliocostal distance and vertebral and non-vertebral fractures in patients seen in a clinical setting. METHODS: Patient data were obtained from the Canadian Database of Osteoporosis and Osteopenia (CANDOO). A total of 549 patients including 508 women and 41 men participated in this cross-sectional study. There were 142 women and 18 men with prevalent vertebral fractures, and 185 women and 21 men with prevalent non-vertebral fractures. RESULTS: In women multivariable regression analysis showed that iliocostal distance was negatively associated with the number of vertebral fractures (-0.18, CI: -0.27, -0.09; adjusted for bone mineral density at the Ward's triangle, epilepsy, cerebrovascular disease, inflammatory bowel disease, etidronate use, and calcium supplement use) and for the number of non-vertebral fractures (-0.09, CI: -0.15, -0.03; adjusted for bone mineral density at the trochanter, cerebrovascular disease, inflammatory bowel disease, and etidronate use). However, in men, multivariable regression analysis did not demonstrate a significant association between iliocostal distance and the number of vertebral and non-vertebral fractures. CONCLUSIONS: The examination of iliocostal distance may be a useful clinical tool for assessment of the possibility of vertebral fractures. The identification of high-risk patients is important to effectively use the growing number of available osteoporosis therapies

The association between timed up and go test and history of falls: The Tromsø study

BACKGROUND: Fall-related injuries in older adults are a major health problem. Although the aetiology of falls is multifactorial, physical factors are assumed to contribute significantly. The "Timed up and go test" (TUG) is designed to measure basic mobility function. This report evaluates the association between TUG times and history of falls. METHODS: A retrospective, observational, population-based study was conducted on 414 men and 560 women with mean age 77.5 (SD 2.3). TUG time and falls during the previous 12 months were recorded. Covariates were age, sex, medical history and health-related mobility problems. Means, confidence intervals and test characteristics for TUG were calculated. Odds ratios and influence of covariates were examined by logistic regression. RESULTS: The mean TUG time was 11.1s (SD 2.5) among male non-fallers and 13.0s (SD 7.8) among fallers. The difference was 1.9s (95%CI 0.9–3.0). The odds ratio for fallers being in the upper quartile was 2.1 (95%CI 1.4–3.3). Adjusted for covariates, the odds ratio was (OR = 1.8, 95%CI 1.1–2.9). The corresponding mean was 13.0s (SD 5.74) among female non-fallers and 13.9s (SD 8.5) among fallers. The difference was 0.9 (95%CI -0.3–2.1). The odds ratio for fallers being in upper quartile was 1.0 (95%CI 0.7–1.4). The area under the ROC curve was 0.50 (95%CI 0.45–0.55) in women and 0.56 (95%CI 0.50–0.62) in men. CONCLUSION: TUG is statistically associated with a history of falls in men but not in women. The ability to classify fallers is poor, and the clinical value of the association is therefore limited

On State-Space Reduction in Multi-Strain Pathogen Models, with an Application to Antigenic Drift in Influenza A

Many pathogens exist in phenotypically distinct strains that interact with each other through competition for hosts. General models that describe such multi-strain systems are extremely difficult to analyze because their state spaces are enormously large. Reduced models have been proposed, but so far all of them necessarily allow for coinfections and require that immunity be mediated solely by reduced infectivity, a potentially problematic assumption. Here, we suggest a new state-space reduction approach that allows immunity to be mediated by either reduced infectivity or reduced susceptibility and that can naturally be used for models with or without coinfections. Our approach utilizes the general framework of status-based models. The cornerstone of our method is the introduction of immunity variables, which describe multi-strain systems more naturally than the traditional tracking of susceptible and infected hosts. Models expressed in this way can be approximated in a natural way by a truncation method that is akin to moment closure, allowing us to sharply reduce the size of the state space, and thus to consider models with many strains in a tractable manner. Applying our method to the phenomenon of antigenic drift in influenza A, we propose a potentially general mechanism that could constrain viral evolution to a one-dimensional manifold in a two-dimensional trait space. Our framework broadens the class of multi-strain systems that can be adequately described by reduced models. It permits computational, and even analytical, investigation and thus serves as a useful tool for understanding the evolution and ecology of multi-strain pathogens