Generalized reliability based on distances.

The intraclass correlation coefficient (ICC) is a classical index of measurement reliability. With the advent of new and complex types of data for which the ICC is not defined, there is a need for new ways to assess reliability. To meet this need, we propose a new distance-based ICC (dbICC), defined in terms of arbitrary distances among observations. We introduce a bias correction to improve the coverage of bootstrap confidence intervals for the dbICC, and demonstrate its efficacy via simulation. We illustrate the proposed method by analyzing the test-retest reliability of brain connectivity matrices derived from a set of repeated functional magnetic resonance imaging scans. The Spearman-Brown formula, which shows how more intensive measurement increases reliability, is extended to encompass the dbICC.

A Time-Varying Measure of Dyadic Synchrony for Three-Dimensional Motion.

We propose a novel approach to the analysis of synchronized three-dimensional motion in dyads. Motion recorded at high time resolution, as with a gaming device, is preprocessed in each of the three spatial dimensions by spline smoothing. Synchrony is then defined, at each time point, as the cosine between the two individuals' estimated velocity vectors. The approach is extended to allow a time lag, allowing for the analysis of leader-follower dynamics. Mean square cosine over the time range is proposed as a scalar summary of dyadic synchrony, and this measure is found to be positively associated with cognitive empathy.

Two-way principal component analysis for matrix-variate data, with an application to functional magnetic resonance imaging data.

Many modern neuroimaging studies acquire large spatial images of the brain observed sequentially over time. Such data are often stored in the forms of matrices. To model these matrix-variate data we introduce a class of separable processes using explicit latent process modeling. To account for the size and two-way structure of the data, we extend principal component analysis to achieve dimensionality reduction at the individual level. We introduce necessary identifiability conditions for each model and develop scalable estimation procedures. The method is motivated by and applied to a functional magnetic resonance imaging study designed to analyze the relationship between pain and brain activity.

Cross-sectional versus longitudinal designs for function estimation, with an application to cerebral cortex development.

Motivated by studies of the development of the human cerebral cortex, we consider the estimation of a mean growth trajectory and the relative merits of cross-sectional and longitudinal data for that task. We define a class of relative efficiencies that compare function estimates in terms of aggregate variance of a parametric function estimate. These generalize the classical design effect for estimating a scalar with cross-sectional versus longitudinal data, and are shown to be bounded above by it in certain cases. Turning to nonparametric function estimation, we find that longitudinal fits may tend to have higher aggregate variance than cross-sectional ones, but that this may occur because the former have higher effective degrees of freedom reflecting greater sensitivity to subtle features of the estimand. These ideas are illustrated with cortical thickness data from a longitudinal neuroimaging study.

Form follows function: Morphological and immunohistological insights into epithelial-mesenchymal transition characteristics of tumor buds.

In cancer biology, the architectural concept "form follows function" is reflected by cell morphology, migration, and epithelial-mesenchymal transition protein pattern. In vivo, features of epithelial-mesenchymal transition have been associated with tumor budding, which correlates significantly with patient outcome. Hereby, the majority of tumor buds are not truly detached but still connected to a major tumor mass. For detailed insights into the different tumor bud types and the process of tumor budding, we quantified tumor cells according to histomorphological and immunohistological epithelial-mesenchymal transition characteristics. Three-dimensional reconstruction from adenocarcinomas (pancreatic, colorectal, lung, and ductal breast cancers) was performed as published. Tumor cell morphology and epithelial-mesenchymal transition characteristics (represented by zinc finger E-box-binding homeobox 1 and E-Cadherin) were analyzed qualitatively and quantitatively in a three-dimensional context. Tumor buds were classified into main tumor mass, connected tumor bud, and isolated tumor bud. Cell morphology and epithelial-mesenchymal transition marker expression were assessed for each tumor cell. Epithelial-mesenchymal transition characteristics between isolated tumor bud and connected tumor bud demonstrated no significant differences or trends. Tumor cell count correlated significantly with epithelial-mesenchymal transition and histomorphological characteristics. Regression curve analysis revealed initially a loss of membranous E-Cadherin, followed by expression of cytoplasmic E-Cadherin and subsequent expression of nuclear zinc finger E-box-binding homeobox 1. Morphologic changes followed later in this sequence. Our data demonstrate that connected and isolated tumor buds are equal concerning immunohistochemical epithelial-mesenchymal transition characteristics and histomorphology. Our data also give an insight in the process of tumor budding. While there is a notion that the epithelial-mesenchymal transition zinc finger E-box-binding homeobox 1-E-Cadherin cascade is initiated by zinc finger E-box-binding homeobox 1, our results are contrary and outline other possible pathways influencing the regulation of E-Cadherin.

Pointwise influence matrices for functional-response regression.

We extend the notion of an influence or hat matrix to regression with functional responses and scalar predictors. For responses depending linearly on a set of predictors, our definition is shown to reduce to the conventional influence matrix for linear models. The pointwise degrees of freedom, the trace of the pointwise influence matrix, are shown to have an adaptivity property that motivates a two-step bivariate smoother for modeling nonlinear dependence on a single predictor. This procedure adapts to varying complexity of the nonlinear model at different locations along the function, and thereby achieves better performance than competing tensor product smoothers in an analysis of the development of white matter microstructure in the brain.

Methods for scalar-on-function regression.

Recent years have seen an explosion of activity in the field of functional data analysis (FDA), in which curves, spectra, images, etc. are considered as basic functional data units. A central problem in FDA is how to fit regression models with scalar responses and functional data points as predictors. We review some of the main approaches to this problem, categorizing the basic model types as linear, nonlinear and nonparametric. We discuss publicly available software packages, and illustrate some of the procedures by application to a functional magnetic resonance imaging dataset.

Can school counselors deliver cognitive-behavioral treatment for social anxiety effectively? A randomized controlled trial.

BACKGROUND: Social anxiety disorder (SAD) typically onsets in adolescence and is associated with multiple impairments. Despite promising clinical interventions, most socially anxious adolescents remain untreated. To address this clinical neglect, we developed a school-based, 12-week group intervention for youth with SAD, Skills for Academic and Social Success (SASS). When implemented by psychologists, SASS has been found effective. To promote dissemination and optimize treatment access, we tested whether school counselors could be effective treatment providers. METHOD: We randomized 138, ninth through 11th graders with SAD to one of three conditions: (a) SASS delivered by school counselors (C-SASS), (b) SASS delivered by psychologists (P-SASS), or (c) a control condition, Skills for Life (SFL), a nonspecific counseling program. Blind, independent, evaluations were conducted with parents and adolescents at baseline, post-intervention, and 5 months beyond treatment completion. We hypothesized that C-SASS and P-SASS would be superior to the control, immediately after treatment and at follow-up. No prediction was made about the relative efficacy of C-SASS and P-SASS. RESULTS: Compared to controls, adolescents treated with C-SASS or P-SASS experienced significantly greater improvement and reductions of anxiety at the end of treatment and follow-up. There were no significant differences between SASS delivered by school counselors and psychologists. CONCLUSION: With training, school counselors are effective treatment providers to adolescents with social anxiety, yielding benefits comparable to those obtained by specialized psychologists. Questions remain regarding means to maintain counselors' practice standards without external support.

Psychometric validation of a German language version of a PROM for urethral stricture surgery and preliminary testing of supplementary ED and UI constructs.

PURPOSE: To validate a German language version of the patient-reported outcome measurement (PROM) following urethral stricture surgery (USS) in a cohort of men undergoing one-stage buccal mucosa graft urethroplasty (BMGU) for urethral stricture. Furthermore, to explore the responsiveness of erectile function (EF) and urinary incontinence (UI) constructs in the context of this intervention. METHODS: The USS-PROM captures voiding symptoms (ICIQ-MLUTS) and health-related quality of life (HRQoL) (EQ-5D). To evaluate EF and UI, the IIEF-5 and ICIQ-UI SF were included. Between March 2012 and April 2013, all patients undergoing BMGU at our institution were prospectively enrolled in this study. Psychometric assessment included internal consistency, test-retest reliability, criterion validity and responsiveness. RESULTS: Ninety-three men completed the USS-PROM before and 3 months after surgery, with 40 (43 %) also completing the USS-PROM 6 months after surgery to assess reliability. Internal consistency: for the ICIQ-MLUTS, Cronbach's α was 0.83. The test-retest intraclass correlation coefficient was 0.94. There was a negative correlation between change in ICIQ-MLUTS total score and change in Q max (r = -0.40). All values exceeded our predefined thresholds. Significant improvements of voiding symptoms and HRQoL demonstrate responsiveness to change (all p values <0.001). While ICIQ-UI scores did not change (p > 0.05), IIEF-5 scores improved significantly (p = 0.048). CONCLUSIONS: The German language USS-PROM shows similar psychometric properties to the English language version. This instrument can be improved by assessing EF by the use of IIEF-5. Further studies with larger patient cohorts are needed to evaluate the significance of measuring UI in urethroplasty patients.

Cross-validation and hypothesis testing in neuroimaging: An irenic comment on the exchange between Friston and Lindquist et al.

The "ten ironic rules for statistical reviewers" presented by Friston (2012) prompted a rebuttal by Lindquist et al. (2013), which was followed by a rejoinder by Friston (2013). A key issue left unresolved in this discussion is the use of cross-validation to test the significance of predictive analyses. This note discusses the role that cross-validation-based and related hypothesis tests have come to play in modern data analyses, in neuroimaging and other fields. It is shown that such tests need not be suboptimal and can fill otherwise-unmet inferential needs.

Quantile rank maps: a new tool for understanding individual brain development.

We propose a novel method for neurodevelopmental brain mapping that displays how an individual's values for a quantity of interest compare with age-specific norms. By estimating smoothly age-varying distributions at a set of brain regions of interest, we derive age-dependent region-wise quantile ranks for a given individual, which can be presented in the form of a brain map. Such quantile rank maps could potentially be used for clinical screening. Bootstrap-based confidence intervals are proposed for the quantile rank estimates. We also propose a recalibrated Kolmogorov-Smirnov test for detecting group differences in the age-varying distribution. This test is shown to be more robust to model misspecification than a linear regression-based test. The proposed methods are applied to brain imaging data from the Nathan Kline Institute Rockland Sample and from the Autism Brain Imaging Data Exchange (ABIDE) sample.

Parent training for preschool ADHD: a randomized controlled trial of specialized and generic programs.

BACKGROUND: The 'New Forest Parenting Package' (NFPP), an 8-week home-based intervention for parents of preschoolers with attention-deficit/hyperactivity disorder (ADHD), fosters constructive parenting to target ADHD-related dysfunctions in attention and impulse control. Although NFPP has improved parent and laboratory measures of ADHD in community samples of children with ADHD-like problems, its efficacy in a clinical sample, and relative to an active treatment comparator, is unknown. The aims are to evaluate the short- and long-term efficacy and generalization effects of NFPP compared to an established clinic-based parenting intervention for treating noncompliant behavior ['Helping the Noncompliant Child' (HNC)] in young children with ADHD. METHODS: A randomized controlled trial with three parallel arms was the design for this study. A total of 164 3-4-year-olds, 73.8% male, meeting DSM-IV ADHD diagnostic criteria were randomized to NFPP (N = 67), HNC (N = 63), or wait-list control (WL, N = 34). All participants were assessed at post-treatment. NFPP and HNC participants were assessed at follow-up in the next school year. Primary outcomes were ADHD ratings by teachers blind to and uninvolved in treatment, and by parents. Secondary ADHD outcomes included clinician assessments, and laboratory measures of on-task behavior and delay of gratification. Other outcomes included parent and teacher ratings of oppositional behavior, and parenting measures. (Trial name: Home-Based Parent Training in ADHD Preschoolers; Registry: ClinicalTrials.gov Identifier: NCT01320098; URL: http://www/clinicaltrials.gov/ct2/show/NCT01320098). RESULTS: In both treatment groups, children's ADHD and ODD behaviors, as well as aspects of parenting, were rated improved by parents at the end of treatment compared to controls. Most of these gains in the children's behavior and in some parenting practices were sustained at follow-up. However, these parent-reported improvements were not corroborated by teacher ratings or objective observations. NFPP was not significantly better, and on a few outcomes significantly less effective, than HNC. CONCLUSIONS: The results do not support the claim that NFPP addresses putative dysfunctions underlying ADHD, bringing about generalized change in ADHD, and its underpinning self-regulatory processes. The findings support documented difficulties in achieving generalization across nontargeted settings, and the importance of using blinded measures to provide meaningful assessments of treatment effects.

Internal urethrotomy in patients with recurrent urethral stricture after buccal mucosa graft urethroplasty.

PURPOSE: To determine the success rate of direct vision internal urethrotomy (DVIU) in the treatment of short stricture recurrence after buccal mucosa graft urethroplasty (BMGU). METHODS: Patients who underwent DVIU for the treatment of short, "veil-like" recurrent urethral strictures (<1 cm) after BMGU between October 2009 and 2013 were retrospectively identified within our urethroplasty database. Stricture recurrence was defined as maximum flow rate (Q max) <15 ml/s and a consecutively verified stricture in a combined retro- and antegrade voiding cystography or cystoscopy at a follow-up visit. The success rate of DVIU was assessed by Kaplan-Meier analysis. Univariable Cox regression analyses evaluated risk factors for stricture recurrence following DVIU. RESULTS: Forty-three patients underwent DVIU for short stricture recurrence after BMGU for bulbar (81.3 %), penile (14.0 %) and membranous (4.7 %) strictures. Relapse had occurred proximally to the buccal mucosa graft in 28 (65.1 %) and distally in 12 (27.9 %) patients, respectively. At a mean follow-up of 11.7 (±9.7) months, stricture recurrence was observed in 48.8 % of our patients. Stricture recurrence was significantly associated with weak urinary stream (9.3 ml/s vs. no recurrence 19.5 ml/s) and patient dissatisfaction (66.7 % vs. no recurrence 18.1 %; both p < 0.001). The overall success rate was 60.5 % 15 months after DVIU. The main limitations of this study are its retrospective design, the small sample size and the short follow-up. CONCLUSIONS: DVIU after BMGU showed a moderate success rate and therefore might be a viable treatment option in selected patients with very short strictures after BMGU. However, longer follow-up is warranted to prove long-term effectiveness.

Staged urethroplasty: comparison of early functional results and quality of life in mesh graft and buccal mucosa technique.

INTRODUCTION: To assess bothersome results of surgery and changes in quality of life (QoL) in patients with two-staged urethral reconstruction. In patients requiring two-staged urethroplasty a functional corpus spongiosum is usually absent, and complications such as urinary dribbling, ejaculation problems and penile deviation can be expected. Data on these complications, patient satisfaction and QoL is limited. MATERIALS AND METHODS: Retrospective analysis by chart review and a standardized questionnaire of 19 consecutive patients with urethral strictures treated by two-staged urethroplasty with buccal-mucosa-graft or mesh-graft. RESULTS: Overall success rate was 84%. Mean follow up 11.2 months, mean length of graft 10 cm (3 cm-18 cm). Urinary stress incontinence occurred in 3 patients (16%). No penile shortening occurred in 9 (47%), no deviation in 11 (58%). Two patients (11%) reported a disturbing alteration in glans sensitivity. Regarding bother by both surgeries and the interval in between, 21% judged the first surgery as hardly or not bothersome. The time in between surgeries was hardly or not bothersome in 52% and the second surgery not or hardly bothersome in 26%. Overall satisfaction with surgery was high (79%) and an improvement in QoL was reported by 63%. Differences between the two groups did not reach statistical significance. CONCLUSION: Two-staged urethroplasty is a viable therapeutic option in patients with severe spongiofibrosis. However, specific counseling for possible complications is of utmost importance.

The ARTUS device: the first feasibility study in human cadavers.

INTRODUCTION: The aim was to perform a feasibility study of the new artificial sphincter device ARTUS in human cadavers. ARTUS is a new electro-mechanical device, which may prevent urethral damage due to a new working principle which is to perform only sequential pressure on successive parts of the urethra. MATERIAL AND METHODS: The implantation of the ARTUS device was performed in six cadavers (3 males, 3 females) with different body mass indices. Subsequently the basic operation data (operation time, cuff size, length of wires, complication) were assessed. RESULTS: The implantation of the ARTUS device is performed easily by the same technique which is commonly used for the AMS 800 implantation. The mean operation time was 20 minutes. The mean cuff size was 4.5 cm in male and 6 cm in female cadavers. The average length of the wires was 12 cm. The necessary subcutaneous pouch had to be bigger than the space used for the tubes of the AMS 800 device. The study is limited by its preclinical setting. CONCLUSIONS: Our results demonstrate that this new artificial urinary sphincter device can be easily implanted. The technical and surgical approaches are similar to those which are applied in the case of the AMS 800 device. Therefore experienced surgeons will be able to adapt their technique easily.

A multivariate distance-based analytic framework for connectome-wide association studies.

The identification of phenotypic associations in high-dimensional brain connectivity data represents the next frontier in the neuroimaging connectomics era. Exploration of brain-phenotype relationships remains limited by statistical approaches that are computationally intensive, depend on a priori hypotheses, or require stringent correction for multiple comparisons. Here, we propose a computationally efficient, data-driven technique for connectome-wide association studies (CWAS) that provides a comprehensive voxel-wise survey of brain-behavior relationships across the connectome; the approach identifies voxels whose whole-brain connectivity patterns vary significantly with a phenotypic variable. Using resting state fMRI data, we demonstrate the utility of our analytic framework by identifying significant connectivity-phenotype relationships for full-scale IQ and assessing their overlap with existent neuroimaging findings, as synthesized by openly available automated meta-analysis (www.neurosynth.org). The results appeared to be robust to the removal of nuisance covariates (i.e., mean connectivity, global signal, and motion) and varying brain resolution (i.e., voxelwise results are highly similar to results using 800 parcellations). We show that CWAS findings can be used to guide subsequent seed-based correlation analyses. Finally, we demonstrate the applicability of the approach by examining CWAS for three additional datasets, each encompassing a distinct phenotypic variable: neurotypical development, Attention-Deficit/Hyperactivity Disorder diagnostic status, and L-DOPA pharmacological manipulation. For each phenotype, our approach to CWAS identified distinct connectome-wide association profiles, not previously attainable in a single study utilizing traditional univariate approaches. As a computationally efficient, extensible, and scalable method, our CWAS framework can accelerate the discovery of brain-behavior relationships in the connectome.

Outcomes after recto-anastomosis fistula repair in patients who underwent radical prostatectomy for prostate cancer.

OBJECTIVES: To assess fistula recurrence rate and health-related quality of life (HRQL) after repair, as well as the impact on continence and erection in patients with recto-anastomotic fistula after radical prostatectomy (RP). In recent publications, the numbers of cases of recto-urinary fistulae after RP are relatively small. Success rates at fistula closure are good; however, data about functional outcomes and HRQL are more restricted. PATIENTS AND METHODS: A retrospective study of patients treated for recto-urethral fistulae after RP between 1993 and 2008. All 17 patients were assessed for fistula recurrence in 2007 and received a standardised non-validated questionnaire to assess HRQL in 2011; furthermore, a patient's chart review was performed. SURGICAL TECHNIQUE: fistula closure was abdominal in 10 patients, perineal in five and combined abdominal and perineal in two, some with tissue interposition. RESULTS: In 2007, follow-up was available for 14 patients, one was deceased and two were lost to follow-up. The mean follow-up was 73.3 months and the mean patient age was 63 years. In two of the 17 patients, rectal injury during the initial surgery was reported; another three had undergone adjuvant radiation therapy (18%). In 2011, another two patients were deceased; the mean (range) follow-up was 99.5 (44-184) months. There was a great improvement in HRQL as compared with before surgery in seven of the 12 evaluable patients, a slight improvement in one and no change in three. In all, eight of the 12 patients were very satisfied with the surgery and four were satisfied. CONCLUSION: Perineal or abdominal fistula repair yields excellent success rates and high patient satisfaction. However, urinary incontinence can be found in some patients postoperatively, requiring further treatment.

Redo-urethroplasty: comparison of early functional results and quality of life in penile and bulbar strictures.

PURPOSE: To assess bothersome results of surgery and changes in quality of life (QoL) in patients with redo-urethroplasty, comparing the functional results of penile and bulbar cases. As after previous urethroplasty scar tissue formation is likely to occur, less favorable functional results than at primary repair could be expected. Yet data on these items for techniques currently used are limited. METHODS: Retrospective analysis with standardized questionnaire including 33 consecutive patients treated with redo-urethroplasty for bulbar or penile strictures. Previous surgeries, recurrence rate, complications, incontinence, erectile function, satisfaction with the surgery and QoL were assessed. RESULTS: Overall success rate was 78.8 %, number of previous open urethroplasty once in 24 patients (72.7 %), and more than once in 9 (27.3 %). Urinary stress incontinence Grade I occurred in 5 patients (15.2 %) and Grade II in 2 patients (6.1 %). In 24 patients (72.7 %), no penile shortening occurred and in 28 (84.8 %), no deviation was observed. Eight patients (24.2 %) reported their glans sensitivity to be altered, in 3 (9.1 %) a disturbing alteration occurred. Overall satisfaction with the surgery was high (70 %), and an improvement in QoL was seen in 72.7 % (24 patients). CONCLUSIONS: Urethroplasty after failed open repair gives good functional results and shows a high patient satisfaction rate. However, results are not quite as good as for primary repair, emphasizing the importance of a successful primary repair.

Optimally weighted L(2) distance for functional data.

Many techniques of functional data analysis require choosing a measure of distance between functions, with the most common choice being L2 distance. In this article we show that using a weighted L2 distance, with a judiciously chosen weight function, can improve the performance of various statistical methods for functional data, including k-medoids clustering, nonparametric classification, and permutation testing. Assuming a quadratically penalized (e.g., spline) basis representation for the functional data, we consider three nontrivial weight functions: design density weights, inverse-variance weights, and a new weight function that minimizes the coefficient of variation of the resulting squared distance by means of an efficient iterative procedure. The benefits of weighting, in particular with the proposed weight function, are demonstrated both in simulation studies and in applications to the Berkeley growth data and a functional magnetic resonance imaging data set.

Functional changes in sleep-related arousal after ketamine administration in individuals with treatment-resistant depression.

The glutamatergic modulator ketamine is associated with changes in sleep, depression, and suicidal ideation (SI). This study sought to evaluate differences in arousal-related sleep metrics between 36 individuals with treatment-resistant major depression (TRD) and 25 healthy volunteers (HVs). It also sought to determine whether ketamine normalizes arousal in individuals with TRD and whether ketamine's effects on arousal mediate its antidepressant and anti-SI effects. This was a secondary analysis of a biomarker-focused, randomized, double-blind, crossover trial of ketamine (0.5 mg/kg) compared to saline placebo. Polysomnography (PSG) studies were conducted one day before and one day after ketamine/placebo infusions. Sleep arousal was measured using spectral power functions over time including alpha (quiet wakefulness), beta (alert wakefulness), and delta (deep sleep) power, as well as macroarchitecture variables, including wakefulness after sleep onset (WASO), total sleep time (TST), rapid eye movement (REM) latency, and Post-Sleep Onset Sleep Efficiency (PSOSE). At baseline, diagnostic differences in sleep macroarchitecture included lower TST (p = 0.006) and shorter REM latency (p = 0.04) in the TRD versus HV group. Ketamine's temporal dynamic effects (relative to placebo) in TRD included increased delta power earlier in the night and increased alpha and delta power later in the night. However, there were no significant diagnostic differences in temporal patterns of alpha, beta, or delta power, no ketamine effects on sleep macroarchitecture arousal metrics, and no mediation effects of sleep variables on ketamine's antidepressant or anti-SI effects. These results highlight the role of sleep-related variables as part of the systemic neurobiological changes initiated after ketamine administration. Clinical Trials Identifier: NCT00088699.