Search

Purpose: This study aimed to develop a fully automated deep learning ciliary body segmentation and assessment approach in three-dimensional ultrasound biomicroscopy (3D-UBM) images., Methods: Each 3D-UBM eye volume was aligned to the optic axis via multiplanar reformatting. Ciliary muscle and processes were manually annotated, and Deeplab-v3+ models with different loss functions were trained to segment the ciliary body (ciliary muscle and processes) in both en face and radial images., Results: We trained and tested the models on 4320 radial and 3864 en face images from 12 cadaver eye volumes. Deep learning models trained on radial images with Dice loss achieved the highest mean F1-score (0.89) for ciliary body segmentation. For three-class segmentation (ciliary muscle, processes, and background), radial images with Dice loss achieved the highest mean F1-score (0.75 for the ciliary process and 0.82 for the ciliary muscle). Part of the ciliary muscle (10.9%) was misclassified as the ciliary process and vice versa, which occurred owing to the difficulty in differentiating the ciliary muscle-processes border, even by experts. Deep learning segmentation made further editing by experts at least seven times faster than a fully manual approach. In eight cadaver eyes, the average ciliary muscle, process, and body volumes were 56 ± 9, 43 ± 13, and 99 ± 18 mm3, respectively. The average surface area of the ciliary muscle, process, and body were 346 ± 45, 363 ± 83, and 709 ± 80 mm2, respectively. We performed transscleral cyclophotocoagulation in cadaver eyes to shrink the ciliary processes. Both manual and automated measurements from deep learning segmentation show a decrease in volume, surface area, and 360° cross-sectional area measurements., Conclusions: The proposed deep learning segmentation of the ciliary body and 3D measurements showed transscleral cyclophotocoagulation-related changes in the ciliary body., Translational Relevance: Automated ciliary body assessment using 3D-UBM has the translational potential for ophthalmic treatment planning and monitoring.

Purpose: Ultrasound biomicroscopy (UBM) is an important ophthalmic imaging modality due to its ability to see behind pigmented iris and to visualize anterior chamber when the eye's transparency is compromised. We created a three-dimensional UBM (3D-UBM) system and acquired example images to illustrate its potential., Methods: A commercial 50-MHz two-dimensional UBM (2D-UBM) system was attached to a precision translation stage and translated across the eye to acquire an image volume. The stage was mounted on a surgical microscope, which enabled safe, stable positioning. Image processing steps included image alignment, noise reduction, and calibration. 3D visualization included alignment of the optic axis, multiplanar reformatting at arbitrary orientations, and volume rendering with optimized transfer functions. Scans were performed on cadaver and rabbit eyes., Results: 3D-UBM allowed visualization of the anterior segment tissues within a 3D anatomical context, unlike 2D-UBM. En face views and interactive slicer operations suggested an ability to plan and assess treatments, including lens placement and microcatheter cannulation of Schlemm's canal. Interactive software allowed us to make accurate measurements of tissue structures (e.g., iridocorneal angles, cyst volumes). In addition, unique measurements of ciliary tissues included single ciliary process volumes of 0.234 ± 0.093 mm3 with surface areas of 3.02 ± 1.07 mm2 and ciliary muscle volume of 67.87 mm3., Conclusions: 3D-UBM imaging of the anterior segment can be used to enable unique visualization and quantification of anterior segment structures., Translational Relevance: 3D-UBM provides informative 3D imaging of tissues in the eye that are invisible to light to potentially provide physicians with improved diagnosis, treatment planning, and treatment assessment as compared to conventional 2D-UBM.

Purpose: To study the effect of decentration and tilt of the type I Boston keratoprosthesis (KPro) on image quality in both aphakic and pseudophakic eyes., Methods: An optical ray-tracing program was used to simulate the image projected onto the retina in an eye with a perfectly centered KPro, and in eyes with varying degrees of KPro decentration and tilt. Decentration was modeled along a typical white-to-white distance of 12.0 mm, and the corresponding tilt was calculated assuming a radius of curvature of 8.0 mm, the radius of curvature of the backplate of the KPro. Both aphakic and pseudophakic eyes were simulated, and the corresponding modulation transfer function curves, point spread functions, and astigmatism were analyzed., Results: The perfectly centered KPro produced a high-quality image with no induced astigmatism. Increasing decentration beyond approximately 0.5 mm resulted in poorer image quality with a more pronounced effect in the presence of an intraocular lens. Using models of the normal eye as a threshold, image degradation due to decentration becomes clinically significant at approximately 1.4 mm and 0.9 mm for the aphakic and pseudophakic cases, respectively. Astigmatism introduced by decentration is approximately 0.25 D cylinders at those thresholds., Conclusions: Decentration of up to 0.5 mm had no significant impact on image quality and an attempt at good intraoperative centration of the KPro within this range is important. Conversely, decentration of 0.9 mm or more during surgical implantation can result in significant degradation in retinal image quality including astigmatism. The effect is greater in the pseudophakic eye.

Biostatisticians recognize the importance of precise definitions of technical terms in randomized controlled clinical trial (RCCT) protocols, statistical analysis plans, and so on, in part because definitions are a foundation for subsequent actions. Imprecise definitions can be a source of controversies about appropriate statistical methods, interpretation of results, and extrapolations to larger populations. This paper presents precise definitions of some familiar terms and definitions of some new terms, some perhaps controversial. The glossary contains definitions that can be copied into a protocol, statistical analysis plan, or similar document and customized. The definitions were motivated and illustrated in the context of a longitudinal RCCT in which some randomized enrollees are non-adherent, receive a corrupted treatment, or withdraw prematurely. The definitions can be adapted for use in a much wider set of RCCTs. New terms can be used in place of controversial terms, for example, subject. We define terms specifying a person's progress through RCCT phases and that precisely define the RCCT's phases and milestones. We define terms that distinguish between subsets of an RCCT's enrollees and a much larger patient population. 'The intention-to-treat (ITT) principle' has multiple interpretations that can be distilled to the definitions of the 'ITT analysis set of randomized enrollees'. Most differences among interpretations of 'the' ITT principle stem from an RCCT's primary objective (mainly efficacy versus effectiveness). Four different 'authoritative' definitions of ITT analysis set of randomized enrollees illustrate the variety of interpretations. We propose a separate specification of the analysis set of data that will be used in a specific analysis. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Stroke is a devastating complication of sickle cell anemia (SCA) with high recurrence if untreated. Chronic transfusions reduce recurrent strokes but have associated morbidities including iron overload. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) was a multicenter phase 3 randomized trial comparing standard treatment (transfusions/chelation) to alternative treatment (hydroxyurea/phlebotomy) for children with SCA, stroke, and iron overload. SWiTCH was a noninferiority trial with a composite primary end point, allowing an increased stroke risk but requiring superiority for removing iron. Subjects on standard treatment received monthly transfusions plus daily deferasirox iron chelation. Subjects on alternative treatment received hydroxyurea plus overlap transfusions during dose escalation to maximum tolerated dose (MTD), followed by monthly phlebotomy. Subjects on standard treatment (N = 66) maintained 30% sickle hemoglobin (HbS) and tolerated deferasirox at 28.2 ± 6.0 mg/kg/d. Subjects on alternative treatment (N = 67) initiated hydroxyurea and 60 (90%) reached MTD at 26.2 ± 4.9 mg/kg/d with 29.1% ± 6.7% fetal hemoglobin (HbF). Adjudication documented no strokes on transfusions/chelation but 7 (10%) on hydroxyurea/phlebotomy, still within the noninferiority stroke margin. The National Heart, Lung, and Blood Institute closed SWiTCH after interim analysis revealed equivalent liver iron content, indicating futility for the composite primary end point. Transfusions and chelation remain a better way to manage children with SCA, stroke, and iron overload.

Background: Stroke occurs in 5-10% of children with sickle cell anemia (SCA) and has a high (>50%) risk of recurrence without therapy. Chronic monthly erythrocyte transfusions effectively prevent recurrent stroke, but their long-term use is limited by serious side effects, including iron overload. An alternative to transfusion for secondary stroke prevention in SCA is needed, especially one that also improves the management of iron overload., Methods: Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) is an NHLBI-sponsored Phase III multicenter randomized controlled clinical trial for children with SCA, stroke, and iron overload (NCT00122980). The primary goal of SWiTCH is to compare 30 months of alternative therapy (hydroxyurea and phlebotomy) with standard therapy (transfusions and chelation) for the prevention of secondary stroke and reduction of transfusional iron overload., Discussion: SWiTCH has several distinctive study features including novel methodological and design components: (1) composite primary endpoint including both stroke recurrence rate and iron burden; (2) non-inferiority design with an "acceptable" increased stroke risk; (3) transfusion goals based on current academic community practices; (4) special oversight for the enrollment and randomization process; (5) overlap treatment period within the alternative treatment arm; (6) masking of the overall trial Principal Investigator to treatment results; (7) inclusive independent stroke adjudication process for all suspected new neurological events; and (8) periodic therapeutic phlebotomy program to alleviate iron overload., Conclusion: Investigation of alternative treatments in SWiTCH could lead to changes in the management of cerebrovascular disease for selected patients with SCA, stroke, and iron overload., (Copyright © 2011 Wiley-Liss, Inc.)

Stroke is a devastating complication of sickle cell anemia (SCA), affecting 5% to 10% of patients before adulthood. Several candidate genetic polymorphisms have been proposed to affect stroke risk, but few have been validated, mainly because previous studies were hampered by relatively small sample sizes and the absence of additional patient cohorts for validation testing. To verify the accuracy of proposed genetic modifiers influencing stroke risk in SCA, we performed genotyping for 38 published single nucleotide polymorphisms (SNPs), as well as α-thalassemia, G6PD A(-) variant deficiency, and β-globin haplotype in 2 cohorts of children with well-defined stroke phenotypes (130 stroke, 103 nonstroke). Five polymorphisms had significant influence (P < .05): SNPs in the ANXA2, TGFBR3, and TEK genes were associated with increased stroke risk, whereas α-thalassemia and a SNP in the ADCY9 gene were linked with decreased stroke risk. Further investigation at these genetic regions may help define mutations that confer stroke risk or protection in children with SCA.

Missing not at random (MNAR) post-dropout missing data from a longitudinal clinical trial result in the collection of "biased data," which leads to biased estimators and tests of corrupted hypotheses. In a full rank linear model analysis the model equation, E[Y] = Xβ, leads to the definition of the primary parameter β = (X'X)(-1)X'E[Y], and the definition of linear secondary parameters of the form θ = Lβ = L(X'X)(-1)X'E[Y], including, for example, a parameter representing a "treatment effect." These parameters depend explicitly on E[Y], which raises the questions: What is E[Y] when some elements of the incomplete random vector Y are not observed and MNAR, or when such a Y is "completed" via imputation? We develop a rigorous, readily interpretable definition of E[Y] in this context that leads directly to definitions of β, Bias(β) = E[β] - β, Bias(θ) = E[θ] - Lβ, and the extent of hypothesis corruption. These definitions provide a basis for evaluating, comparing, and removing biases induced by various linear imputation methods for MNAR incomplete data from longitudinal clinical trials. Linear imputation methods use earlier data from a subject to impute values for post-dropout missing values and include "Last Observation Carried Forward" (LOCF) and "Baseline Observation Carried Forward" (BOCF), among others. We illustrate the methods of evaluating, comparing, and removing biases and the effects of testing corresponding corrupted hypotheses via a hypothetical but very realistic longitudinal analgesic clinical trial.

Chronic transfusions to maintain haemoglobin S (HbS) < or =30% are the mainstay of treatment for children with sickle cell anaemia (SCA) and previous stroke. This HbS target is often hard to maintain, however, and values achieved in current practice are unknown. In preparation for the Phase III Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial, we collected data on 295 children with SCA and stroke who received transfusions at 23 institutions. The overall average pre-transfusion %HbS was 35 +/- 11% (institutional range 22-51%). Receiving scheduled transfusions on time was the most predictive variable for maintaining HbS at the < or =30% goal.

The linear mixed model has become a widely used tool for longitudinal analysis of continuous variables. The use of regression splines in these models offers the analyst additional flexibility in the formulation of descriptive analyses, exploratory analyses and hypothesis-driven confirmatory analyses. We propose a method for fitting piecewise polynomial regression splines with varying polynomial order in the fixed effects and/or random effects of the linear mixed model. The polynomial segments are explicitly constrained by side conditions for continuity and some smoothness at the points where they join. By using a reparameterization of this explicitly constrained linear mixed model, an implicitly constrained linear mixed model is constructed that simplifies implementation of fixed-knot regression splines. The proposed approach is relatively simple, handles splines in one variable or multiple variables, and can be easily programmed using existing commercial software such as SAS or S-plus. The method is illustrated using two examples: an analysis of longitudinal viral load data from a study of subjects with acute HIV-1 infection and an analysis of 24-hour ambulatory blood pressure profiles.

In this article, we present methodology for making inferences about projected completors in the presence of attrition. The approach is motivated by a clinical trial that investigates a treatment for disability among individuals who sustain severe head injuries. Although most studies attempt to make inferences about the entire study population, our application poses important scientific questions targeting individuals who are likely to complete the study or to remain on protocol for a specified time period. We propose using measures of each individual's dropout inclination to identify projected completors and then building a stratified response model based on projected completion status. We present several prediction measures along with procedures for evaluating accuracy with respect to observed dropout. Estimation of model parameters proceeds using maximum likelihood and restricted maximum likelihood methods. We illustrate the utility of our proposed analysis by using the motivating disability data example.

Estimating the correlation coefficient between two outcome variables is one of the most important aspects of epidemiological and clinical research. A simple Pearson's correlation coefficient method is usually employed when there are complete independent data points for both outcome variables. However, researchers often deal with correlated observations in a longitudinal setting with missing values where a simple Pearson's correlation coefficient method cannot be used. General linear mixed models (GLMM) techniques were used to estimate correlation coefficients in a longitudinal data set with missing values. A random regression mixed model with unstructured covariance matrix was employed to estimate correlation coefficients between concentrations of HIV-1 RNA in blood and seminal plasma. The effects of CD4 count and antiretroviral therapy were also examined. We used data sets from three different centres (650 samples from 238 patients) where blood and seminal plasma HIV-1 RNA concentrations were collected from patients; 137 samples from 90 different patients without antiviral therapy and 513 samples from 148 patients receiving therapy were considered for analysis. We found no significant correlation between blood and semen HIV-1 RNA concentration in the absence of antiviral therapy. However, a moderate correlation between blood and semen HIV-1 RNA was observed among subjects with lower CD4 counts receiving therapy. Our findings confirm and extend the idea that the concentrations of HIV-1 in semen often differ from the HIV-1 concentration in blood. Antiretroviral therapy administered to subjects with low CD4 counts result in sufficient concomitant reduction of HIV-1 in blood and semen so as to improve the correlation between these compartments. These results have important implications for studies related to the sexual transmission of HIV, and development of HIV prevention strategies., (Copyright 2003 John Wiley & Sons, Ltd.)

Objectives: Although hydroxyurea is effective in treating adults with sickle-cell anemia (SCA), there is concern that it may adversely affect growth in children. We report the growth characteristics of patients in the Phase I-II pediatric hydroxyurea trial (HUG-KIDS) before and during treatment at the maximum tolerated dose for one year., Study Design: Children and adolescents with SCA (n = 68), aged 5 to 16 years at baseline, reached the maximum tolerated dose and had serial height, weight, and Tanner stage measurements. Data from the Cooperative Study of Sickle Cell Disease (CSSCD) were used for comparison. Mixed-effects models were used to compare serial measurements as a function of age and group., Results: In girls, there were no significant differences in height or weight among the pretreatment, on-treatment, and CSSCD groups. Compared with the CSSCD group, HUG-KIDS boys were heavier starting at age 9 years, and pretreatment HUG-KIDS boys were taller starting at age 7 years. The Tanner stage transitions took place at appropriate ages., Conclusions: Hydroxyurea treatment had no adverse effect on height or weight gain or pubertal development in school-aged children with SCA.

In the phase I/II pediatric hydroxyurea safety trial (HUG-KIDS), school-aged children with sickle cell anemia receiving hydroxyurea at the maximally tolerated dose (MTD) had variable increases in the percentage of fetal hemoglobin (%HbF). To identify predictors of the HbF response to hydroxyurea therapy, baseline clinical and laboratory values (age, sex, hemoglobin concentration, %HbF, reticulocytes, white blood cell [WBC], platelets, and serum chemistries), as well as treatment variables (number of toxicities, noncompliance, MTD dose, and MTD blood counts) were analyzed in 53 HUG-KIDS children who achieved MTD. Baseline %HbF values (P =.001), baseline hemoglobin concentration (P =.01), MTD dose (P =.02), and compliance (P =.02) were significantly associated with a higher %HbF at MTD; in contrast, age, sex, number of toxicities, and other baseline hematologic parameters were not. After adjusting for variations in baseline %HbF, the baseline reticulocyte count (P =.05) and baseline WBC count (P =.05) were also significantly associated with a higher %HbF at MTD. Hydroxyurea-induced increases in the hemoglobin concentration and mean corpuscular volume (both higher absolute values at MTD and larger positive changes from baseline values), as well as hydroxyurea-induced decreases in reticulocytes and WBC count, were significantly associated with a higher %HbF at MTD. These data suggest that selected baseline laboratory parameters, a higher MTD dose with attention to compliance, and greater therapy-related changes in blood counts may predict the HbF response to hydroxyurea therapy for children with sickle cell anemia. The HbF response to hydroxyurea is variable and complex, however, and even children with low baseline %HbF values can develop substantial increases in %HbF at MTD.

Scientists may wish to analyze correlated outcome data with constraints among the responses. For example, piecewise linear regression in a longitudinal data analysis can require use of a general linear mixed model combined with linear parameter constraints. Although well developed for standard univariate models, there are no general results that allow a data analyst to specify a mixed model equation in conjunction with a set of constraints on the parameters. We resolve the difficulty by precisely describing conditions that allow specifying linear parameter constraints that insure the validity of estimates and tests in a general linear mixed model. The recommended approach requires only straightforward and noniterative calculations to implement. We illustrate the convenience and advantages of the methods with a comparison of cognitive developmental patterns in a study of individuals from infancy to early adulthood for children from low-income families.

Objective: To develop a model to predict transmission of HIV-1 from men to women., Design: HIV-1 in seminal plasma, and endocervical CCR5 receptors were correlated with epidemiological studies of HIV-1 transmission to develop a probabilistic model., Settings: Semen samples were collected from patient subjects in Seattle Washington, Chapel Hill, North Carolina, and St. Gallen, Switzerland. Endocervical biopsy specimens were obtained from women in Chicago, Illinois., Participants: Eighty-six men (not receiving antiretroviral therapy) in whom CD4 cell count and semen volume were available, and 24 women in whom the number of endocervical CCR5 receptors were determined., Main Outcome Measures: Prediction of transmission of HIV-1 from men to women per episode of vaginal intercourse based on the absolute burden of HIV (volume x HIV RNA copies/ml seminal plasma)., Results: The model suggests efficient heterosexual transmission of HIV-1 when semen viral burden is high. When semen contains 100 000 copies of non-syncytium-inducing (NSI) HIV RNA the probability of HIV-1 transmission is 1 per 100 episodes of intercourse; conversely, with 1000 copies NSI HIV RNA in semen, transmission probability is 3 per 10 000 episodes of intercourse., Conclusions: This model links biological and epidemiological data related to heterosexual HIV-1 transmission. The model can be used to estimate transmission of HIV from men with high semen viral burden from inflammation, or reduced burden after antiretroviral therapy. The results offer a biological explanation for the magnitude of the HIV epidemic in places where earlier studies have shown men have high semen viral burden, such as in sub-Saharan Africa. The model can be used to develop and test HIV-1 prevention strategies.

Previous studies have determined the short-term toxicity profile, laboratory changes, and clinical efficacy associated with hydroxyurea (HU) therapy in adults with sickle cell anemia. The safety and efficacy of this agent in pediatric patients with sickle cell anemia has not been determined. Children with sickle cell anemia, age 5 to 15 years, were eligible for this multicenter Phase I/II trial. HU was started at 15 mg/kg/d and escalated to 30 mg/kg/d unless the patient experienced laboratory toxicity. Patients were monitored by 2-week visits to assess compliance, toxicity, clinical adverse events, growth parameters, and laboratory efficacy associated with HU treatment. Eighty-four children were enrolled between December 1994 and March 1996. Sixty-eight children reached maximum tolerated dose (MTD) and 52 were treated at MTD for 1 year. Significant hematologic changes included increases in hemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin, and fetal hemoglobin parameters, and decreases in white blood cell, neutrophil, platelet, and reticulocyte counts. Laboratory toxicities typically were mild, transient, and were reversible upon temporary discontinuation of HU. No life-threatening clinical adverse events occurred and no child experienced growth failure. This Phase I/II trial shows that HU therapy is safe for children with sickle cell anemia when treatment was directed by a pediatric hematologist. HU in children induces similar laboratory changes as in adults. Phase III trials to determine if HU can prevent chronic organ damage in children with sickle cell anemia are warranted.

Discriminant analysis is commonly used to classify an observation into one of two (or more) populations on the basis of correlated measurements. Classical discriminant analysis approaches require complete data for all observations. Our extension enables the use of all available longitudinal data, regardless of completeness. Traditionally a linear discriminant function assumes a common unstructured covariance matrix for both populations, which may be taken from a multivariate model. Here, we can model the correlated measurements and use a structured covariance in the discriminant function. We illustrate cases in which the estimated covariance structure is either compound symmetric, heterogeneous compound symmetric or heterogeneous autoregressive. Thus a structured covariance is incorporated into the discrimination process in contrast to standard discriminant analysis methodology. Simulations are performed to obtain a true measure of the effect of structure on the error rate. In addition, the usual multivariate expected value structure is altered. The impact on the discrimination process is contrasted when using the multivariate and random-effects covariance structures and expected values. The random-effects covariance structure leads to an improvement in the error rate in small samples. To illustrate the procedure we consider repeated measurements data from a clinical trial comparing two active treatments; the goal is to determine if the treatment could be unblinded based on repeated anxiety score measurements.

Objectives: This article describes a catheter system designed to create linear atrial lesions and identifies electrophysiologic markers that are associated with the creation of linear lesions., Background: Atrial fibrillation (Afib) is the most common arrhythmia in humans and causes a significant morbidity. The success of surgical interventions has provided the impetus for the development of a catheter-based approach for the ablation of Afib., Methods: We tested a catheter system with 24 4-mm ring electrodes that can create loops in the atria. The electrodes can be used to record electrical activity and deliver radiofrequency power for ablation. In 33 dogs, 82 linear lesions were generated using three power titration protocols: fixed levels, manual titration guided by local electrogram activity and temperature control. Bipolar activity was recorded from the 24 electrodes before, during and after lesion generation. Data were gathered regarding lesion contiguity, transmurality and dimensions; the changes in local electrical activity amplitude; the incidence rate of rapid impedance rises and desiccation or char formation; and rhythm outcomes., Results: Catheter deployment usually requires <60 s. Linear lesions (12 to 16 cm in length and 6 +/- 2 mm wide) can be generated in 24 to 48 min without moving the catheter. Effective lesion formation can be predicted by a decrease of greater than 50% in the amplitude of bipolar recordings. Splitting or fragmentation of the electrogram and increasing pacing threshold (3.1 +/- 3.3 mV to 7.1 +/- 3.8 mV, p < 0.01) are indicative of effective lesion formation. Impedance rises and char formation occurred at 91 +/- 12 degrees C. Linear lesion creation does not result in the initiation of Afib. However, atrial flutter was recorded after the completion of the final lesion in 3/12 hearts. When using temperature control, no char was noted in the left atrium, whereas 8% of the right atrium burns had char., Conclusions: This adjustable loop catheter forces the atrial tissue to conform around the catheter and is capable of producing linear, contiguous lesions up to 16 cm long with minimal effort and radiation exposure. Pacing thresholds and electrogram amplitude and character are markers of effective lesion formation. Although Afib could not be induced after lesion set completion, sustained atrial flutter could be induced in 25% of the hearts.

MSQ, the 16-item Migraine-Specific Quality-of-Life Questionnaire (Version 1.0), was developed by Glaxo Wellcome Inc. to assess the effect of migraine and its treatment on patients' health-related quality of life (HR-QOL). The MSQ was hypothesised to measure 3 meaningful dimensions: (i) Role Function-Restrictive; (ii) Role Function-Preventive; and (iii) Emotional Function. The objective of this research was to further investigate the number of dimensions as well as the items contained in each dimension through principal components factor analysis of clinical trial data. Secondary objectives were to determine whether the factor structure changed in post-treatment visits compared with screening visits, to make recommendations for coding the MSQ when the patient did not have a migraine in the previous 4 weeks, and to modify the MSQ if so indicated by this research. Results supported the existence of 3 distinct factors which agreed strongly with the hypothesised dimensions. The analysis of post-treatment data suggested that the underlying factor structure of the MSQ varies as a result of treatment. Based on evaluations of the 'did not have a migraine' response, it was concluded that it be dropped from the MSQ. All these changes have been incorporated into MSQ (Version 2.0) which is being evaluated in studies to determine if its psychometric properties are different than the properties of the previous version.

The purpose of this paper is to demonstrate the use of the mixed general linear model (MixMod) for modeling development of sleep-wake behaviors in preterm infants. The mixed general linear model allows the concurrent identification of both group and individual developmental patterns in longitudinal data sets with inconsistently timed data, irregularly timed data, and randomly missing values. This statistical technique is well suited to data from preterm infants because these infants enter and leave longitudinal studies at varying times depending on their health status. One sleep organizational variable--the regularity of respiration in quiet sleep--obtained from a study of 37 preterm infants was used as an example. Seven infant characteristics were used as covariates. The various steps involved in conducting a mixed model analysis of this variable are illustrated. The strengths and limitations of this technique are discussed.

Objectives: This study assessed the effects of the Safe Dates program on the primary and secondary prevention of adolescent dating violence., Methods: Fourteen schools were randomly allocated to treatment conditions. Eighty percent (n=1886) of the eighth and ninth graders in a rural county completed baseline questionnaires, and 1700 (90%) completed follow-up questionnaires., Results: Treatment and control groups were comparable at baseline. In the full sample at follow-up, less psychological abuse, sexual violence, and violence perpetrated against the current dating partner were reported in treatment than in control schools. In a subsample of adolescents reporting no dating violence at baseline (a primary prevention subsample), there was less initiation of psychological abuse in treatment than in control schools. In a subsample of adolescents reporting dating violence at baseline (a secondary prevention subsample), there was less psychological abuse and sexual violence perpetration reported at follow-up in treatment than in control schools. Most program effects were explained by changes in dating violence norms, gender stereotyping, and awareness of services., Conclusions: The Safe Dates program shows promise for preventing dating violence among adolescents.

In longitudinal studies with incomplete data, where the number of time points can become numerous, it is often advantageous to model the covariance matrix. We describe several covariance models (for example, mixed models, compound symmetry, AR(1)-type models, and combination models) that offer parsimonious alternatives to unstructured sigma. We evaluate each covariance model with longitudinal data concerning cholesterol as the repeated outcome measure. We discuss strategies for deciding the 'best' model and show a graphical technique for judging goodness-of-fit of covariance models.

Maximum likelihood techniques using the EM algorithm are applied to correlated normally distributed survival data from a placebo-controlled, double-blind, dose-ranging crossover study to assess the short-term efficacy of an antianginal drug in patients with chronic stable angina. Censoring was informative and nonterminal and was not due to death or withdrawal from the study. Unlike previous approaches these techniques are mathematically and computationally tractable, do not require computations of high-dimensional integrals, and do not require the inversion of large matrices.

Effects of increased dietary chloride and reduced sodium and potassium ion concentrations on coxofemoral joint conformation, as assessed by radiography, were examined in growing dogs. Dietary electrolyte balance was quantified by dietary anion gap (DAG), defined as Na+ + K+ - Cl- in milli-equivalents per 100 g of food. Diets had anion gap ranging from 8 to 41 mEq/100 g of food. One hundred sixty-seven pups from 27 litters representing 5 breeds were studied during the period of rapid growth. The extent of subluxation of the femoral head was measured on radiographs, using the method of Norberg. On average, less subluxation of the femoral head (P < 0.05) was observed when diets with lower DAG were fed. Differences in DAG balance did not result in different rates of weight gain; therefore, the reduction in coxofemoral joint subluxation attributable to low DAG was unrelated to weight gain. Norberg angles measured at 30 weeks of age were highly correlated with coxofemoral joint status at 2 years of age, as measured by the Swedish diagnostic system and the scoring system of the Orthopedic Foundation for Animals (lrl > or = 0.70, P < 0.0002, n = 24). This diet-related improvement in coxofemoral joint subluxation would be expected, on average, to delay or mitigate the characteristic clinical and radiographic signs of hip dysplasia in growing dogs.

Longitudinal designs are important in medical research and in many other disciplines. Complete longitudinal studies, in which each subject is evaluated at each measurement occasion, are often very expensive and motivate a search for more efficient designs. Recently developed statistical methods foster the use of intentionally incomplete longitudinal designs that have the potential to be more efficient than complete designs. Mixed models provide appropriate data analysis tools. Fixed effect hypotheses can be tested via a recently developed test statistic, FH. An accurate approximation of the statistic's small sample non-central distribution makes power computations feasible. After reviewing some longitudinal design terminology and mixed model notation, this paper summarizes the computation of FH and approximate power from its non-central distribution. These methods are applied to obtain a large number of intentionally incomplete full-span designs that are more powerful and/or less costly alternatives to a complete design. The source of the greater efficiency of incomplete designs and potential fragility of incomplete designs to randomly missing data are discussed.

Forty-eight 8-week-old Labrador Retrievers were allotted to 2 groups of 24 dogs each; 1 group was fed ad libitum and the other group was given 25% less of the same feed until the dogs were 2 years old. Radiography of the hip joints was done when the dogs were 30, 42, 54, 78, and 104 weeks old. Subluxation was measured by the Norberg angle on radiographs made with the dog in the standard (extended limb) position. Independent of age at which the radiography was done, there was less subluxation of the femoral heads in the limit-fed dogs. Using the Swedish method of hip joint evaluation on the same radiographs, it was found that fewer dogs on limited food intake had signs of hip dysplasia. Radiographs done when dogs were 2 years old, for all the methods used (Norberg angle in standard and frog-limb position, the Orthopedic Foundation for Animals [OFA] score, and the Swedish score), revealed less hip dysplasia (less joint subluxation and less degenerative joint disease) in the limit-fed dogs. Using the OFA method, 7 of the 24 limit-fed dogs and 16 of the 24 ad libitum-fed dogs were diagnosed as having hip dysplasia. Similarly, using the Swedish method, 5 of the 24 limit-fed dogs and 18 of the 24 ad libitum-fed dogs were diagnosed as having hip dysplasia. The food-intake-related differences were significant both for the OFA score and for the Swedish score.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between average and peak personal exposure to nitrogen dioxide and urinary excretion of hydroxyproline and desmosine was investigated in a population of preschool children and their mothers. Weekly average personal nitrogen dioxide exposures for subjects who resided in homes with one or more potential nitrogen dioxide source (e.g., a kerosene space heater, gas stove, or tobacco smoke) ranged between 16.3 and 50.6 ppb (30.6 and 95.1 micrograms/m3) for children and between 16.9 and 44.1 ppb (12.8 and 82.9 micrograms/m3) for mothers. In these individuals, the hydroxyproline-to-creatinine and desmosine-to-creatinine ratios were unrelated to personal nitrogen dioxide exposure--even though continuous monitoring documented home nitrogen dioxide concentration peaks of 100-475 ppb lasting up to 100 h in duration. Significantly higher hydroxyproline-to-creatinine and desmosine-to-creatinine ratios were observed in children, compared with mothers (p < .001 and .003, respectively).

Excessive active absorption of sodium is a unique abnormality of the airway epithelium in patients with cystic fibrosis. This defect is associated with thickened mucus and poor clearance of airway secretions and may contribute to the pulmonary disease in these patients. To study whether the inhibition of excessive absorption of sodium might affect the course of lung disease in cystic fibrosis, we performed a double-blind, crossover trial comparing aerosolized amiloride (5 mmol per liter; 3.5 ml four times daily), a sodium-channel blocker, with vehicle alone. Fourteen of the 18 adult patients initially enrolled in the study completed the one-year trial (25 weeks for each treatment). The mean (+/- SEM) loss of forced vital capacity (FVC) was reduced from 3.39 +/- 1.13 ml per day during treatment with vehicle alone to 1.44 +/- 0.67 ml per day during treatment with amiloride (P less than 0.04). A measured index of sputum viscosity and elasticity was abnormal during treatment with vehicle alone and improved during treatment with amiloride. Calculated indexes of mucociliary and cough clearance also improved during amiloride treatment. No systemic, respiratory, or subjective toxic effects of amiloride were noted. We conclude from this preliminary study that aerosolized amiloride can be safely administered to adults with cystic fibrosis. The slowing of the loss of FVC and the improvement in sputum viscosity and elasticity suggest a beneficial clinical effect. Aerosolized amiloride deserves further evaluation in the treatment of lung disease in patients with cystic fibrosis.

Relational database software has become popular for the management of certain types of commercial data. Its use is being given serious consideration in the management of data from clinical trials. Relational systems have a number of advantages over hierarchical or network systems for some types of data. However, as illustrated by an example, the data from clinical trials typically have an inherent hierarchical structure. The incorporation of hierarchically structured data into a relational database raises difficult problems of data integrity versus the complexity of the database structure. These problems, together with the long execution times of many relational operations, indicate that relational systems are not necessarily well suited for clinical trials data management.

A stochastic model is presented for the analysis of incomplete repeated-measures experiments. The general linear model is used to relate the response measures to other variables which are thought to account for inherent variation; an autoregressive moving average (ARMA) time series representation is used to model disturbance terms. Maximum likelihood estimation procedures are considered, and the properties of these estimators are derived. It is concluded that while the assumptions underpinning the ARMA covariance models may be somewhat restrictive, they provide a useful inferential vehicle, particularly in the presence of missing values.

An energy supplementation program provided free of charge a low energy (15 kcal) and a high energy (350 kcal) soft drink to two group of sugarcane workers in Guatemala. The high energy supplement supplied 550 kcal/day on a weekly basis. The workers tended to be moderately energy deficient before supplementation. Significant increases in total daily energy intake were obtained with the high energy supplement, but by less than the energy content of the supplement. Workers maintained energy balance with supplementation. The degree of substitution with energy supplementation was not related to the energy intake status of the workers' households. These households did generally not improve their energy intake status with worker supplementation.

The importance of season as a variable in total IgE production in normal children is demonstrated. Recent history of allergen exposure as well as respiratory infection, both of which are seasonally determined, should be considered in evaluating serum IgE values.

To document passive smoke exposure, we measured concentrations of serum cotinine, a major metabolite of nicotine, in 38 young children and compared the results with the smoking histories of home residents. Cotinine was detected in 26 children (68%), of which ten had no household exposure according to a questionnaire. The serum cotinine concentration was significantly elevated in blacks compared with whites after controlling for the number of smokers in the home. After stratifying by race, there was a significant direct correlation between the serum cotinine concentration and the number of smokers in the home, the amount smoked by the mother, and the amount smoked by others in the home. We conclude that the serum cotinine concentration is a useful indicator of the actual exposure of young children to tobacco smoke and that unexplained racial differences in cotinine levels exist.

Spirometry was performed longitudinally over a period of 8 yr on 72 children (29 black females, 26 black males, 9 white females, and 8 white males) starting as early as 3 yr of age. Weighted straight-line regressions of 6 maximal expiratory flow-volume parameters--forced vital capacity (FVC), forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), forced expiratory flow during the middle half of the FVC (FEF25-75), and maximal expiratory flows after 50 and 75% of the FVC had been exhaled (Vmax50 and Vmax75, respectively) - on height were computed and were found to describe adequately the data over a height range of 100 to 150 cm. Statistical comparisons of regression lines revealed significant differences for FVC and FEV1 when white females were compared with white males, white females with black females, and white males with black males, but not for black females with black males. Regressions of FEF25-75 and Vmax50 for black females were significantly lower than for white females, and those for white males were lower than those for white females, but no differences were detected when black females and white males were compared with black males. Only white females compared with black females revealed significant differences for Vmax75. There were no significant differences for any of the comparisons for PEF. The data presented expand the age range for evaluating lung function in children, indicate the feasibility of testing pre-school-age subjects, and provide new approaches to analysis of longitudinally collected information.

Results from longitudinal and cross-sectional studies of pulmonary function are often compared. However, previous studies in adults suggest that results from longitudinal and cross-sectional studies are different and may not be comparable. In order to evaluate these differences further, prospectively collected data in a group of children were analyzed by both longitudinal and cross-sectional methods. Spirometry was performed longitudinally over a period of 8 years on 58 healthy children. Straight-line regressions of expiratory flow-volume parameters on height were computed by averaging the individual regression lines for each child. A cross-sectional sample from these same children was analyzed and compared to the longitudinal analysis. For all expiratory flow-volume parameters, the cross-sectional analysis resulted in a significantly greater increase in growth with increasing height than the longitudinal analysis (P less than 0.005 for slope for all parameters except PEFR, P less than 0.05 and Vmax75, P less than 0.01). These differences cannot be explained by learning or horse-racing effects, loss to follow-up, or regression to the mean; however, they could be explained by cohort changes, time trends of pulmonary function, differences in the weighted averages used in the two analyses, or incorrect modeling. These observations indicate that comparisons between cross-sectional and longitudinal investigations must be made cautiously. These data do not support many of the reasons suggested for the differences in previous reports. It is recommended that studies of pulmonary function use a control group and investigate the groups at the same time and in the same manner.

This study surveyed 102 patients with cleft lip, cleft palate, or cleft lip and cleft palate (ages 13 to 19) and their parents to assess satisfaction with appearance, speech ability, and intelligibility. The data were based upon standardized interviews conducted at a cleft palate treatment center, using simple questions with high face validity. Surgical experience was high among this sample, as reflected by the finding that the majority of patients (55.7%) had had three or more operations on the face or mouth. Patient ratings of facial appearance showed that most patients were very pleased (59.3%) or moderately pleased (13.2%); others were somewhat (18.7%) or very (8.8%) disappointed. Many parents indicated that their children expressed occasional (22.0%) or frequent (27.5%) concerns about appearance. Nearly all patients (91.9%) felt that their operations had accomplished what they expected, though some of the cleft lip patients (35.7%) and their parents (43.9%) were less than very pleased with the appearance of the lip. When asked how pleased they were with the way they presently talked, most patients (69.1%) were very pleased, though some disappointment was expressed. Although often pleased with their current speech status, many patients rated themselves as only moderately understandable (19.1%) or as not understandable (8.5%). No significant gender effects were found in satisfaction, appearance, or speech ratings. There were no significant differences found between parent and child ratings. The findings indicate that at a center delivering team-based cleft palate care, both adolescent patients and their parents have considerable concerns about appearance and speech results.

A study was conducted in two elementary schools in Mexico City to determine values for pulmonary function tests in school-aged residents of Mexico City. The schools were located in Xalostoc, a highly industrialized area of Mexico City, and San Lorenzo, a suburban area of the city. Although data regarding atmospheric pollution were not available, there is an acknowledged higher level of macroenvironmental air pollution in Xalostoc. Pulmonary function tests were performed on 468 children in San Lorenzo and 405 children in Xalostoc. No differences between residents of the two communities for acute or chronic respiratory conditions were detected by questionnaire. The pulmonary function data demonstrate that boys have larger forced vital capacities (FVC) and forced expiratory flows over the middle half of the FVC (FEF25-75) than girls. Slopes of regression lines for FVC but not for FEF25-75 are greater in boys and girls from Xalostoc than in boys and girls from San Lorenzo. This suggests that young children from Xalostoc may experience ill effects of air pollution but develop catch-up growth later. There were no important community or gender effects on slopes of regression lines for height and weight on age. In general, the regression lines for FVC and FEF25-75 were below regression lines reported for children of Mexican ancestry living at sea level.

We examined the extent of correlation between home air nicotine levels and urine cotinine/creatinine ratios (CCR) in 27 children who attended a research day care program where they were not exposed to environmental tobacco smoke (ETS) during the daytime hours. Average concentrations of nicotine in home air were determined by active air sampling during the evening and night hours on 2 consecutive days. Urine samples for cotinine and creatinine determinations were collected before, during, and after the two sampling periods. In addition, four sequential weekly urine samples for CCR were obtained from study children to determine the extent to which single determinations of CCR were representative for individual children. Fifteen children resided in homes with smokers, and 12 did not. Urine CCR consistently distinguished most exposed and unexposed children. However, three exposed children had urine CCRs that clustered routinely around the criterion CCR (30 ng/mg cotinine-creatinine) that best distinguished exposed and unexposed children. In children exposed to ETS in the home, there was a significant correlation between average home air nicotine levels and the average logarithm of urine CCR the two mornings after the home air monitoring periods (r = 0.68; p = 0.006). In study children, urine CCRs were remarkably stable over the 1-month observation period. Rank correlation coefficients for sequential weekly determinations of CCR were consistently greater than r = 0.88; p less than 0.0001.

Etiology, symptomatology, and host factors were studied in 184 children referred to a teaching hospital for evaluation in an attempt to classify chronic or potentially chronic lung disease. A standardized historical questionnaire, physical findings, chest radiographs, and a laboratory panel identified a diagnosis that could be related directly or indirectly to chronic lung disease in 22% of the subjects. Among the remaining 78%, bronchiectasis was found in 9%, chronic pneumonia in 9%, chronic diseases with wheezing in 56%, and no significant lower respiratory disease in 4%. Analysis of cases with no apparent etiology revealed that the majority of patients had historical evidence of wheezing; often this previously had not been appreciated. Laboratory tests, such as eosinophil count and immunoglobulin E (IgE) testing, did not differentiate between wheezing and nonwheezing patients. Spirometric evaluation was limited because most subjects were younger than 5 years old. For the same reason, testing for bronchial hyperreactivity was not done. This study reemphasizes that wheezing is a major symptom of chronic lung disease in childhood and provides an outline for its evaluation. Although clinical airways reactivity, as exemplified by wheezing, proved to be the most prominent host defect found in this study, its nature, genetic or otherwise, remains to be defined.