Analysis of longitudinal binary data with missing data due to dropouts

Longitudinal binary data from clinical trials with missing observations are frequently analyzed by using the Last Observation Carry Forward (LOCF) method for imputing missing values at a visit (e.g., the prospectively defined primary visit time point for analysis at the end of treatment period). Usually, to understand time trend in treatment response, analyses are also performed separately on data at intermediate time points. The objective of such analyses is to estimate the proportion of "response" at a time point and then to compare two treatment groups (e.g., drug vs. placebo) by testing for the difference in the two proportions of response. The commonly used methods are Fisher's exact test, chi-squared test, Cochran-Mantel-Haenszel test, and logistic regression. Analyses based on the Observed Cases (OC) data are usually also performed and compared with those obtained by LOCF. Another approach that is gaining popularity (after the introduction of PROC GENMOD by the SAS Institute) is to use the method of Generalized Estimating Equations (GEE) with a view to include all repeated observations in the analysis in a more comprehensive manner. It is now well recognized, however, that results obtained by these methods are susceptible to bias, depending on the "missing data mechanism." Of particular concern is the bias introduced by NMAR dropouts. Because there is no one method to satisfactorily handle dropouts in data analysis, consensus is gathering toward doing analyses by several methods (including methods to handle NMAR dropouts) to evaluate sensitivity of results to model assumptions. In this article, we demonstrate application of the following methods for handling dropouts in longitudinal binary data: Generalized Linear Mixture Models (GLMM) (for handling NMAR dropouts), Weighted GEE (for handling MAR dropouts), and GEE (MCAR dropouts). The results are also compared with those obtained by logistic regression (univariate) on both LOCF and OC data.     

Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene

PURPOSE: To investigate the clinical features of subjects with glaucoma with the E50K mutation in the optineurin (OPTN) gene and to compare the onset, severity, and clinical course of these patients with a control group of subjects with glaucoma without this mutation. METHODS: The phenotype of well-characterized subjects from Moorfields Eye Hospital, London, who had been identified as carrying the OPTN E50K mutation was examined. A wide range of structural, psychophysical, and demographic factors were then compared with those in a control group of subjects with glaucoma without this mutation. RESULTS: Eleven subjects with glaucoma with the E50K mutation (nine in two families and two sporadic cases) were studied. All 11 subjects had normal tension glaucoma (NTG), with presenting and highest IOP of 15.3 +/- 3.0 and 16.5 +/- 2.5 mm Hg (+/-SD) on diurnal testing. Compared with 87 NTG control subjects who did not have this mutation, subjects with E50K presented at a younger age (40.8 +/- 15 years, P = 0.0001) and had more advanced optic disc cupping (mean cup-disc ratio +/- SD 0.86 +/- 0.1, P = 0.001) and smaller neuroretinal rim area (+/-SD; 0.5 +/- 0.28 mm2, P = 0.001) at diagnosis. The rate of filtration surgery performed for progressive visual field loss in those with and without the E50K mutation was 72.7% and 25.3%, respectively (P = 0.003), and all subjects with E50K were found to have progressing visual fields. In addition, seven E50K mutation-carrying individuals in two families (age range, 23-58 years) presented with normal optic discs and visual fields and, as yet, no signs of glaucoma. CONCLUSIONS: In this study, subjects with glaucoma who had the OPTN E50K mutation were found to have NTG that appeared to be more severe than that in a control group of subjects with NTG without this mutation. The findings emphasize the importance of early detection and treatment of glaucoma in such individuals, to minimize visual loss.     

Posterior sternoclavicular dislocation in a rugby player as a cause of silent vascular compromise: a case report

Case and Results: We describe a case in which there was no clinical evidence of complication, although CT imaging revealed complete obstruction of the brachiocephalic vein and impingement of the aorta. This required open reduction and a novel fixation technique was employed. The reduction was stable at 8 month follow up appointment as evidenced by CT scan.

Conclusions: We acknowledge that this type of complication is well recognised but emphasise that it should not be managed complacently. A high index of suspicion is required to determine the presence of serious complications in this type of injury, which may manifest insidiously.

     

High prevalence of penicillin resistance and comparative in vitro activity of various antibiotics in clinical isolates of streptococcus pneumoniae isolated in the Province of Hainaut during winter 2004

A total of 154 isolates of Streptococcus pneumoniae obtained from 8 different centres in the province of Hainaut were included in this study. The susceptibilities to penicillin, amoxicillin, cefuroxime, ciprofloxacin, moxifloxacin, erythromycin and tetracycline were determined by a microdilution technique following NCCLS recommendations. Decreased susceptibility to penicillin was 32.5% (23.4% intermediate and 9.1% high-level). The other insusceptibility rates were as follows: amoxicillin 1.9% [0% Resistance (R)], cefuroxime 23.4% (R 22.1%), ciprofloxacin 9.1% (R 1.3%), erythromycin 39.6% (R 38.3%), and tetracycline 31.8% (R 30.5%). No decreased susceptibility was found for moxifloxacin. MICs of amoxicillin, cefuroxime, erythromycin and tetracycline rose with those of penicillin for penicillin-insusceptible isolates. Most penicillin-insusceptible isolates remained fully susceptible to amoxicillin (94%), while moxifloxacin and ciprofloxacin kept an activity on 100% and 92% of these isolates respectively. Phenotypes with triple or quadruple insusceptibility were present in 31.2% of the isolates. Penicillin-insusceptible isolates showed a co-insusceptibility of 36.7% to erythromycin, 30.0% to tetracycline and 3.3% to ciprofloxacin.     

Emphysematous gastritis

Emphysematous gastritis is a rare condition in which gas collects within the stomach wall secondary to infection by gas-producing organisms. The authors report a case of an 82-year-old diabetic man admitted for altered mental status, fever, and leukocytosis. Intramural air within the gastric wall was incidentally found by computed tomography. The case is discussed and differential diagnosis, early diagnosis, and outcome are reviewed.     

Recombinant modified vaccinia Ankara primes functionally activated CTL specific for a melanoma tumor antigen epitope in melanoma patients with a high risk of disease recurrence

Recombinant plasmid DNA and attenuated poxviruses are under development as cancer and infectious disease vaccines. We present the results of a phase I clinical trial of recombinant plasmid DNA and modified vaccinia Ankara (MVA), both encoding 7 melanoma tumor antigen cytotoxic T lymphocyte (CTL) epitopes. HLA-A*0201-positive patients with surgically treated melanoma received either a "prime-boost" DNA/MVA or a homologous MVA-only regimen. Ex vivo tetramer analysis, performed at multiple time points, provided detailed kinetics of vaccine-driven CTL responses specific for the high-affinity melan-A(26-35) analogue epitope. Melan-A26-35-specific CTL were generated in 2/6 patients who received DNA/MVA (detectable only after the first MVA injection) and 4/7 patients who received MVA only. Ex vivo ELISPOT analysis and in vitro proliferation assays confirmed the effector function of these CTL. Responses were seen in smallpox-vaccinated as well as vaccinia-naive patients, as defined by anti-vaccinia antibody responses demonstrated by ELISA assay. The observations that 1) CTL responses were generated to only 1 of the recombinant epitopes and 2) that the magnitude of these responses (0.029-0.19% CD8(+) T cells) was below the levels usually seen in acute viral infections suggest that to ensure high numbers of CTL specific for multiple recombinant epitopes, a deeper understanding of the interplay between CTL responses specific for the viral vector and recombinant epitopes is required.     

Elevated sphingomyelinase activity and ceramide concentration in serum of patients undergoing high dose spatially fractionated radiation treatment: implications for endothelial apoptosis

Spatially fractionated high dose (grid) radiation treatment (SFGRT) involves irradiation of bulky tumors with one high, grid-delivered, dose of 15 Gy followed by multiple consecutive doses of 2 Gy each. The goal of this study is to determine the effect of this treatment on serum ceramide content and to investigate possible involvement of ceramide in tumor regression after SFGRT. Serum ceramide and Secretory SMase (S-SMase) were quantified in 11 patients before and at 24, 48 and 72 h after the dose of 15 Gy. Furthermore, LDL particles were isolated from the serum and their apoptotic ability was tested in human endothelial cells by TUNEL assay. Sixty seven per cent (6/8) of the patients with partial (PR) or complete (CR) response showed statistically significant increase in serum ceramide levels. Of the nonresponders in the study, none showed an elevation in ceramide. S-SMase activity underwent similar changes. LDL particles from serum of patients collected 72 hours after SFGRT sensitized the endothelial cells to undergo apoptosis in response to 5 Gy radiation that by itself had only modest effect on cell death. Independent elevation of ceramide content of endothelial cells that were otherwise resistant to radiation-induced cell death also was sufficient to sensitize these cells to apoptosis. Serum S-SMase activity and ceramide content increase following SFGRT and correlate with the clinical response. Apparently, these changes are in the LDL-associated ceramide and may contribute to better tumor reduction after SFGRT, due to the ability of LDL-derived ceramide to sensitize endothelial cells for apoptosis.