MODELING DIFFERENTIATED TREATMENT EFFECTS FOR MULTIPLE OUTCOMES DATA

Multiple outcomes data are commonly used to characterize treatment effects in medical research, for instance, multiple symptoms to characterize potential remission of a psychiatric disorder. Often either a global, i.e. symptom-invariant, treatment effect is evaluated. Such a treatment effect may over generalize the effect across the outcomes. On the other hand individual treatment effects, varying across all outcomes, are complicated to interpret, and their estimation may lose precision relative to a global summary. An effective compromise to summarize the treatment effect may be through patterns of the treatment effects, i.e. "differentiated effects." In this paper we propose a two-category model to differentiate treatment effects into two groups. A model fitting algorithm and simulation study are presented, and several methods are developed to analyze heterogeneity presenting in the treatment effects. The method is illustrated using an analysis of schizophrenia symptom data.

QUANTIFYING UNCERTAINTY IN GENOTYPE CALLS

Genome-wide association studies (GWAS) are used to discover genes underlying complex, heritable disorders for which less powerful study designs have failed in the past. The number of GWAS has skyrocketed recently with findings reported in top journals and the mainstream media. Mircorarrays are the genotype calling technology of choice in GWAS as they permit exploration of more than a million single nucleotide polymorphisms (SNPs)simultaneously. The starting point for the statistical analyses used by GWAS, to determine association between loci and disease, are genotype calls (AA, AB, or BB). However, the raw data, microarray probe intensities, are heavily processed before arriving at these calls. Various sophisticated statistical procedures have been proposed for transforming raw data into genotype calls. We find that variability in microarray output quality across different SNPs, different arrays, and different sample batches has substantial inuence on the accuracy of genotype calls made by existing algorithms. Failure to account for these sources of variability, GWAS run the risk of adversely affecting the quality of reported findings. In this paper we present solutions based on a multi-level mixed model. Software implementation of the method described in this paper is available as free and open source code in the crlmm R/BioConductor.

ON MARGINALIZED MULTILEVEL MODELS AND THEIR COMPUTATION

Clustered data analysis is characterized by the need to describe both systematic variation in a mean model and cluster-dependent random variation in an association model. Marginalized multilevel models embrace the robustness and interpretations of a marginal mean model, while retaining the likelihood inference capabilities and flexible dependence structures of a conditional association model. Although there has been increasing recognition of the attractiveness of marginalized multilevel models, there has been a gap in their practical application arising from a lack of readily available estimation procedures. We extend the marginalized multilevel model to allow for nonlinear functions in both the mean and association aspects. We then formulate marginal models through conditional specifications to facilitate estimation with mixed model computational solutions already in place. We illustrate this approach on a cerebrovascular deficiency crossover trial.

RANDOM EFFECTS MODELS IN A META-ANALYSIS OF THE ACCURACY OF DIAGNOSTIC TESTS WITHIN A GOLD STANDARD IN THE PRESENCE OF MISSING DATA

In evaluating the accuracy of diagnosis tests, it is common to apply two imperfect tests jointly or sequentially to a study population. In a recent meta-analysis of the accuracy of microsatellite instability testing (MSI) and traditional mutation analysis (MUT) in predicting germline mutations of the mismatch repair (MMR) genes, a Bayesian approach (Chen, Watson, and Parmigiani 2005) was proposed to handle missing data resulting from partial testing and the lack of a gold standard. In this paper, we demonstrate an improved estimation of the sensitivities and specificities of MSI and MUT by using a nonlinear mixed model and a Bayesian hierarchical model, both of which account for the heterogeneity across studies through study-specific random effects. The methods can be used to estimate the accuracy of two imperfect diagnostic tests in other meta-analyses when the prevalence of disease, the sensitivities and/or the specificities of diagnostic tests are heterogeneous among studies. Furthermore, simulation studies have demonstrated the importance of carefully selecting appropriate random effects on the estimation of diagnostic accuracy measurements in this scenario.

Evaluation of factors affecting speed perception in a driving simulator

The present study was conducted to determine the effects of different variables on the perception of vehicle speeds in a driving simulator. The motivations of the study include validation of the Michigan Technological University Human Factors and Systems Lab driving simulator, obtaining a better understanding of what influences speed perception in a virtual environment, and how to improve speed perception in future simulations involving driver performance measures. Using a fixed base driving simulator, two experiments were conducted, the first to evaluate the effects of subject gender, roadway orientation, field of view, barriers along the roadway, opposing traffic speed, and subject speed judgment strategies on speed estimation, and the second to evaluate all of these variables as well as feedback training through use of the speedometer during a practice run. A mixed procedure model (mixed model ANOVA) in SAS® 9.2 was used to determine the significance of these variables in relation to subject speed estimates, as there were both between and within subject variables analyzed. It was found that subject gender, roadway orientation, feedback training, and the type of judgment strategy all significantly affect speed perception. By using curved roadways, feedback training, and speed judgment strategies including road lines, speed limit experience, and feedback training, speed perception in a driving simulator was found to be significantly improved.

Information processing in long delay memory-guided saccades: further insights from TMS

The performance of memory-guided saccades with two different delays (3 s and 30 s of memorisation) was studied in eight subjects. Single pulse transcranial magnetic stimulation (TMS) was applied simultaneously over the left and right dorsolateral prefrontal cortex (DLPFC) 1 s after target presentation. In both delays, stimulation significantly increased the percentage of error in amplitude of memory-guided saccades. Furthermore, the interfering effect of TMS was significantly higher in the short delay compared to that of the long delay paradigm. The results are discussed in the context of a mixed model of spatial working memory control including two components: First, serial information processing with a predominant role of the DLPFC during the early period of memorisation and, second, parallel information processing, which is independent from the DLPFC, operating during longer delays.

Long-term gas exchange characteristics as marker of deterioration in patients with cystic fibrosis

Background and Aim In patients with cystic fibrosis (CF) the architecture of the developing lungs and the ventilation of lung units are progressively affected, influencing intrapulmonary gas mixing and gas exchange. We examined the long-term course of blood gas measurements in relation to characteristics of lung function and the influence of different CFTR genotype upon this process. Methods Serial annual measurements of PaO2 and PaCO2 assessed in relation to lung function, providing functional residual capacity (FRCpleth), lung clearance index (LCI), trapped gas (VTG), airway resistance (sReff), and forced expiratory indices (FEV1, FEF50), were collected in 178 children (88 males; 90 females) with CF, over an age range of 5 to 18 years. Linear mixed model analysis and binary logistic regression analysis were used to define predominant lung function parameters influencing oxygenation and carbon dioxide elimination. Results PaO2 decreased linearly from age 5 to 18 years, and was mainly associated with FRCpleth, (p < 0.0001), FEV1 (p < 0.001), FEF50 (p < 0.002), and LCI (p < 0.002), indicating that oxygenation was associated with the degree of pulmonary hyperinflation, ventilation inhomogeneities and impeded airway function. PaCO2 showed a transitory phase of low PaCO2 values, mainly during the age range of 5 to 12 years. Both PaO2 and PaCO2 presented with different progression slopes within specific CFTR genotypes. Conclusion In the long-term evaluation of gas exchange characteristics, an association with different lung function patterns was found and was closely related to specific genotypes. Early examination of blood gases may reveal hypocarbia, presumably reflecting compensatory mechanisms to improve oxygenation.

The Car Resequencing Problem with Pull-Off Tables

The car sequencing problem determines sequences of different car models launched down a mixed-model assembly line. To avoid work overloads of workforce, car sequencing restricts the maximum occurrence of labor-intensive options, e.g., a sunroof, by applying sequencing rules. We consider this problem in a resequencing context, where a given number of buffers (denoted as pull-off tables) is available for rearranging a stirred sequence. The problem is formalized and suited solution procedures are developed. A lower bound and a dominance rule are introduced which both reduce the running time of our graph approach. Finally, a real-world resequencing setting is investigated.

Rapid tranquilization of severely agitated patients with schizophrenia spectrum disorders: a naturalistic, rater-blinded, randomized, controlled study with oral haloperidol, risperidone, and olanzapine

INTRODUCTION Agitation is a major problem in acute schizophrenia. Only a few studies have tested antipsychotic agents in severely agitated patients, mainly because of legal issues. Furthermore, most studies were limited to the first 24 hours. We aimed to investigate the efficacy of oral haloperidol, risperidone, and olanzapine in reducing psychotic agitation in severely agitated patients with schizophrenia or schizophreniform or schizoaffective disorder over 96 hours using a prospective, randomized, rater-blinded, controlled design within a naturalistic treatment regimen. METHODS In total, 43 severely agitated patients at acute care psychiatric units were enrolled. Participants were randomly assigned to receive either daily haloperidol 15 mg, olanzapine 20 mg, or risperidone 2 to 6 mg over 5 days. Positive and Negative Syndrome Scale psychotic agitation subscale score was the primary outcome variable. A mixed-model analysis was applied. RESULTS All drugs were effective for rapid tranquilization within 2 hours. Over 5 days, the course differed between agents (P < 0.001), but none was superior. Dropouts occurred only in the risperidone and olanzapine groups. Men responded better to treatment than did women during the initial 2 hours (P = 0.046) as well as over the 5-day course (P < 0.001). No difference between drug groups was observed regarding diazepam or biperiden use. CONCLUSIONS Oral haloperidol, risperidone, and olanzapine seem to be suitable for treating acute severe psychotic agitation in schizophrenia spectrum disorders. Response to oral antipsychotics demonstrated a gender effect with poorer outcome in women throughout the study.

Genome-wide analysis in German shepherd dogs reveals association of a locus on CFA 27 with atopic dermatitis

Humans and dogs are both affected by the allergic skin disease atopic dermatitis (AD), caused by an interaction between genetic and environmental factors. The German shepherd dog (GSD) is a high-risk breed for canine AD (CAD). In this study, we used a Swedish cohort of GSDs as a model for human AD. Serum IgA levels are known to be lower in GSDs compared to other breeds. We detected significantly lower IgA levels in the CAD cases compared to controls (p = 1.1 × 10(-5)) in our study population. We also detected a separation within the GSD cohort, where dogs could be grouped into two different subpopulations. Disease prevalence differed significantly between the subpopulations contributing to population stratification (λ = 1.3), which was successfully corrected for using a mixed model approach. A genome-wide association analysis of CAD was performed (n cases = 91, n controls = 88). IgA levels were included in the model, due to the high correlation between CAD and low IgA levels. In addition, we detected a correlation between IgA levels and the age at the time of sampling (corr = 0.42, p = 3.0 × 10(-9)), thus age was included in the model. A genome-wide significant association was detected on chromosome 27 (praw = 3.1 × 10(-7), pgenome = 0.03). The total associated region was defined as a ~1.5-Mb-long haplotype including eight genes. Through targeted re-sequencing and additional genotyping of a subset of identified SNPs, we defined 11 smaller haplotype blocks within the associated region. Two blocks showed the strongest association to CAD. The ~209-kb region, defined by the two blocks, harbors only the PKP2 gene, encoding Plakophilin 2 expressed in the desmosomes and important for skin structure. Our results may yield further insight into the genetics behind both canine and human AD.

Early changes in biochemical markers of bone formation during teriparatide therapy correlate with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis

Summary Changes of the bone formation marker PINP correlated positively with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis (GIO) who received 18-month treatment with teriparatide, but not with risedronate. These results support the use of PINP as a surrogate marker of bone strength in GIO patients treated with teriparatide. Introduction To investigate the correlations between biochemical markers of bone turnover and vertebral strength estimated by finite element analysis (FEA) in men with GIO. Methods A total of 92 men with GIO were included in an 18-month, randomized, open-label trial of teriparatide (20 μg/day, n = 45) and risedronate (35 mg/week, n = 47). High-resolution quantitative computed tomography images of the 12th thoracic vertebra obtained at baseline, 6 and 18 months were converted into digital nonlinear FE models and subjected to anterior bending, axial compression and torsion. Stiffness and strength were computed for each model and loading mode. Serum biochemical markers of bone formation (amino-terminal-propeptide of type I collagen [PINP]) and bone resorption (type I collagen cross-linked C-telopeptide degradation fragments [CTx]) were measured at baseline, 3 months, 6 months and 18 months. A mixed-model of repeated measures analysed changes from baseline and between-group differences. Spearman correlations assessed the relationship between changes from baseline of bone markers with FEA variables. Results PINP and CTx levels increased in the teriparatide group and decreased in the risedronate group. FEA-derived parameters increased in both groups, but were significantly higher at 18 months in the teriparatide group. Significant positive correlations were found between changes from baseline of PINP at 3, 6 and 18 months with changes in FE strength in the teriparatide-treated group, but not in the risedronate group. Conclusions Positive correlations between changes in a biochemical marker of bone formation and improvement of biomechanical properties support the use of PINP as a surrogate marker of bone strength in teriparatide-treated GIO patients.

A chromosomal region on ECA13 is associated with maxillary prognathism in horses.

Hereditary variations in head morphology and head malformations are known in many species. The most common variation encountered in horses is maxillary prognathism. Prognathism and brachygnathism are syndromes of the upper and lower jaw, respectively. The resulting malocclusion can negatively affect teeth wear, and is considered a non-desirable trait in breeding programs. We performed a case-control analysis for maxillary prognathism in horses using 96 cases and 763 controls. All horses had been previously genotyped with a commercially available 50 k SNP array. We analyzed the data with a mixed-model considering the genomic relationships in order to account for population stratification. Two SNPs within a region on the distal end of chromosome ECA 13 reached the Bonferroni corrected genome-wide significance level. There is no known prognathism candidate gene located within this region. Therefore, our findings in the horse offer the possibility of identifying a novel gene involved in the complex genetics of prognathism that might also be relevant for humans and other livestock species.

Rapid tranquilization of severely agitated patients with schizophrenia spectrum disorders: a naturalistic, rater-blinded, randomized controlled study with oral haloperidol, risperidone, and olanzapine

Agitation is a major problem in acute schizophrenia. Still, only limited evidence exists on antipsychotic efficacy in severely agitated patients after the first 24 hours. We aimed to investigate the efficacy of oral haloperidol, risperidone, and olanzapine in reducing psychotic agitation in severely agitated patients with schizophrenia or schizophreniform or schizoaffective disorder over 96 hours using a prospective, randomized, rater-blinded, controlled design within a naturalistic treatment regimen. We enrolled 43 severely agitated patients at acute care psychiatric units. Participants were randomly assigned to receive either daily haloperidol 15 mg, olanzapine 20 mg, or risperidone 2 – 6 mg over 5 days. Positive and Negative Syndrome Scale psychotic agitation (PANSS-PAS) subscore was the primary outcome variable. A mixed model analyses was applied. All drugs were effective for rapid tranquillization within 2 hours. Over 5 days, the course differed between agents (p < 0.001) but none was superior. Dropouts occurred only in the risperidone and olanzapine groups. Men responded better to treatment than women during the initial 2 hours (p = 0.046) as well as over the 5 day course (p < 0.001). No difference between drug groups was observed regarding diazepam or biperiden use. Oral haloperidol, risperidone, and olanzapine seem to be suitable for treating acute severe psychotic agitation in schizophrenia spectrum disorders. We observed a gender effect with poorer outcome in women.

Ethnic Minority Children’s Active Commuting to School and Association with Physical Activity and Pedestrian Safety Behaviors

Background: Children's active commuting to school, i.e. walking or cycling to school, was associated with greater moderate-to-vigorous physical activity, although studies among ethnic minorities are sparse. Objectives: Among a low-income, ethnic minority sample of fourth grade students from eight public schools, we examined (1) correlates of active commuting to school and (2) the relationship between active commuting to school and moderate-to-vigorous physical activity. Methods: We conducted a cross-sectional analysis of baseline measurements from a sample of participants (n=149) aged 9-12 years from a walk to school intervention study in Houston, Texas. The primary outcome was the weekly rate of active commuting to school. Daily moderate-to-vigorous physical activity, measured by accelerometers, was a secondary outcome. Child self-efficacy (alpha=0.75), parent self-efficacy (alpha=0.88), and parent outcome expectations (alpha=0.78) were independent variables. Participant characteristics (age, gender, race/ethnicity, distance from home to school, acculturation, and BMI percentile) were independent sociodemographic variables. We used mixed-model regression analyses to account for clustering by school and a stepwise procedure with backward elimination of non-significant interactions and covariates to identify significant moderators and predictors. School-level observations of student pedestrians were assessed and compared using chi-square tests of independence. Results: Among our sample, which was 61.7% Latino, the overall rate of active commuting to school was 43%. In the mixed model for active commuting to school, parent self-efficacy (std. beta = 0.18, p=0.018) and age (std. beta = 0.18, p=0.018) were positively related. Latino students had lower rates of active commuting to school than non-Latinos ( 16.5%, p=0.040). Distance from home to school was inversely related to active commuting to school (std. beta = 0.29, p<0.001). In the mixed model for moderate-to-vigorous physical activity, active commuting to school was positively associated (std. beta = 0.31, p <0.001). Among the Latino subsample, child acculturation was negatively associated with active commuting to school (std. beta = -0.23, p=0.01). With regard to school-level pedestrian safety observations, 37% of students stopped at the curb and 2.6% looked left-right-left before crossing the street. Conclusion: Although still below national goals, the rate of active commuting was relatively high, while the rate of some pedestrian safety behaviors was low among this low-income, ethnic minority population. Programs and policies to encourage safe active commuting to school are warranted and should consider the influence of parents, acculturation, and ethnicity.

The nonsteroidal anti-inflammatory drug indomethacin induces heterogeneity in lipid membranes: potential implication for its diverse biological action.

BACKGROUND: The nonsteroidal anti-inflammatory drug (NSAID), indomethacin (Indo), has a large number of divergent biological effects, the molecular mechanism(s) for which have yet to be fully elucidated. Interestingly, Indo is highly amphiphilic and associates strongly with lipid membranes, which influence localization, structure and function of membrane-associating proteins and actively regulate cell signaling events. Thus, it is possible that Indo regulates diverse cell functions by altering micro-environments within the membrane. Here we explored the effect of Indo on the nature of the segregated domains in a mixed model membrane composed of dipalmitoyl phosphatidyl-choline (di16:0 PC, or DPPC) and dioleoyl phosphatidyl-choline (di18:1 PC or DOPC) and cholesterol that mimics biomembranes. METHODOLOGY/PRINCIPAL FINDINGS: Using a series of fluorescent probes in a fluorescence resonance energy transfer (FRET) study, we found that Indo induced separation between gel domains and fluid domains in the mixed model membrane, possibly by enhancing the formation of gel-phase domains. This effect originated from the ability of Indo to specifically target the ordered domains in the mixed membrane. These findings were further confirmed by measuring the ability of Indo to affect the fluidity-dependent fluorescence quenching and the level of detergent resistance of membranes. CONCLUSION/SIGNIFICANCE: Because the tested lipids are the main lipid constituents in cell membranes, the observed formation of gel phase domains induced by Indo potentially occurs in biomembranes. This marked Indo-induced change in phase behavior potentially alters membrane protein functions, which contribute to the wide variety of biological activities of Indo and other NSAIDs.