Identifying subpopulations for subgroup analysis in a longitudinal clinical trial

BackgroundIn a typical clinical trial treatment effects will not be expected to be the same on all of the study participants. As a result, investigators are often tempted to look at the effects of a given treatment in subgroups of patients in order to determine who will benefit the most or the least, especially when the treatment effect in the total sample is insignificant or borderline. This paper aims at demonstrating the application of random effect models as one approach to identify subpopulations suitable for subgroup analysis in a longitudinal study.MethodsData collected from a double-blind randomized controlled trial were used to demonstrate how multilevel modeling using random effects can be used to identify subgroups of postmenopausal women who benefit the most from nonhormonal treatment (gabapentin) of their hot flashes.ResultsWe estimated subject-specific treatment effects and correlated these effects with patient characteristics at baseline. We found that women with a higher severity of hot flashes score at baseline were more likely to have the greatest reduction in hot flashes score from the treatment. Also, women who had a serum creatinine level higher than the median level at baseline demonstrated a greater response to gabapentin compared to the placebo group.ConclusionOur proposed method can help researchers identify patient factors that are associated with differential effect. Those factors are potential areas for further clinical investigation or for constructing subgroups for sub-analysis.     

Nanoparticle Formation of Organic Compounds With Retained Biological Activity

Many pharmaceuticals are formulated as powders to aid drug delivery. A major problem is how to produce powders having high purity, controlled morphology, and retained bioactivity. We demonstrate the use of supercritical carbon dioxide as an antisolvent for meeting this need for two model drug systems, quercetin, a sparingly soluble antioxidant, and short interfering RNA (siRNA), which can silence genes. In both cases we achieve retention of bioactivity as well as a narrow particle size distribution in which the particles are free of impurities.     

Shwachman-Diamond syndrome: an inherited model of aplastic anaemia with accelerated angiogenesis

Bone marrow angiogenesis is increased in myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), but has not been studied in inherited or acquired marrow failure syndromes. Shwachman-Diamond syndrome (SDS) carries a high risk of MDS/AML and is characterised by marrow stromal dysfunction. Compared with controls, SDS patients without MDS/AML had higher marrow microvessel density. Stromal VEGF gene expression, stromal vascular endothelial growth factor (VEGF) secretion and VEGF levels in serum and marrow mononuclear cells were normal. Future studies should investigate the mechanism for increased angiogenesis in SDS, and whether SDS marrow, with its increased angiogenesis, promotes progression of malignant clones.     

US or CT for Diagnosis of Appendicitis in Children and Adults? A Meta-Analysis

PURPOSE: To perform a meta-analysis to evaluate the diagnostic performance of ultrasonography (US) and computed tomography (CT) for the diagnosis of appendicitis in pediatric and adult populations. MATERIALS AND METHODS: Medical literature (from 1986 to 2004) was searched for articles on studies that used US, CT, or both as diagnostic tests for appendicitis in children (26 studies, 9356 patients) or adults (31 studies, 4341 patients). Prospective and retrospective studies were included if they separately reported the rate of true-positive, true-negative, false-positive, and false-negative diagnoses of appendicitis from US and CT findings compared with the positive and negative rates of appendicitis at surgery or follow-up. Clinical variables, technical factors, and test performance were extracted. Three readers assessed the quality of studies. RESULTS: Pooled sensitivity and specificity for diagnosis of appendicitis in children were 88% (95% confidence interval [CI]: 86%, 90%) and 94% (95% CI: 92%, 95%), respectively, for US studies and 94% (95% CI: 92%, 97%) and 95% (95% CI: 94%, 97%), respectively, for CT studies. Pooled sensitivity and specificity for diagnosis in adults were 83% (95% CI: 78%, 87%) and 93% (95% CI: 90%, 96%), respectively, for US studies and 94% (95% CI: 92%, 95%) and 94% (95% CI: 94%, 96%), respectively, for CT studies. CONCLUSION: From the diagnostic performance perspective, CT had a significantly higher sensitivity than did US in studies of children and adults; from the safety perspective, however, one should consider the radiation associated with CT, especially in children.     

Maternal rubella-specific antibody prevalence in Ethiopian infants

In countries with a high transmission rate of rubella the optimal age for universal rubella vaccination of infants is critically dependent upon the rate of loss of maternal antibodies. Few studies have investigated the decay characteristics of such antibodies. Mother:infant pairs were recruited at the Ethio-Swedish Children's Hospital, Addis Ababa, in 1994/95. Rubella antibody levels, determined by radial haemolysis, were available for analysis from 1542 infants aged 0-12 months, with 942 repeat measures, and from 846 mothers. Decay in seropositivity was well described by a delayed exponential function. The proportion seropositive at age 6, 9, or 12 months was 6-13%, 1-4%, or 0-1%, respectively, dependent upon assay cutoff level. Only infant age and mother's antibody level were important predictors of seropositivity. Results suggest that the success of vaccination at age 9 months or above would be little affected by residual maternal antibodies.     

Outcome of isolated antenatal hydronephrosis: a systematic review and meta-analysis

Idiopathic antenatal hydronephrosis (IAHN), defined as antenatal hydronephrosis not associated with other morphologic renal tract abnormalities, is the most common abnormality detected by antenatal ultrasound. We performed a systematic review and meta-analysis to determine the outcome of IAHN. We screened three databases and bibliographies to identify English-language original peer-reviewed papers that reported serial postnatal renal ultrasonography in children with IAHN. Patients who stabilized and/or improved were extracted and pooled according to the individual grading systems used by each study. A systematic analysis of data extracted from 25 articles revealed overall resolution of pelviectasis in milder cases of IAHN (Society of Fetal Urology [SFU] grade 1–2; anterior posterior pelvic diameter [APPD]<12 mm). In contrast, IAHN of higher severity (grades 3–4; APPD>12 mm) resolved with a lower frequency. Meta-analysis of data extracted from seven papers showed stabilization of pelviectasis in 98% of patients with grades 1–2 (95% confidence interval [CI] 0.93–1.0; p =0.0008) and in 51% of patients with grades 3–4 (95% CI 0.34–0.68; p <0.00001). Grades 1–2 pelviectasis was five times more likely to stabilize than grades 3–4 pelviectasis (odds ratio [OR] 4.69; 95% CI 1.73–12.76; p =0.002). We conclude that in patients with IAHN and lesser degrees of pelvic dilatation, pelvic diameter decreases to the normal range or does not worsen with the vast majority of patients. Further studies are needed to define outcomes, particularly in more severe forms of IAHN.     

Creating continuity through mutual assistance: intergenerational reciprocity in four ethnic groups

OBJECTIVES: Our purpose is to examine how culture-specific conceptions of mutual assistance in four ethnic groups reflect the nature of social exchange and its role in creating continuity. METHODS: We conducted five in-depth interviews over a 5-year period with 270 respondents aged 50 and up (59 African Americans, 85 Latinos, 78 Filipino Americans, and 48 Cambodian Americans). We asked both open-ended and semistructured questions to determine how respondents viewed their role in mutual assistance in the family. RESULTS: Mutual assistance was a critical element in intergenerational relations in all four groups, as it represented continuity within the family and was a part of a broader cultural ethos of family relationships. There were differences between groups in overall approach to mutual assistance, the factors to which they assigned the greatest importance, and the degree of dissatisfaction expressed over family relationships. DISCUSSION: Social exchange can be viewed not only as a means by which those who are old maintain power but as a major vehicle for perpetuating continuity across the generations. When social exchange breaks down, elders suffer from loss of power as expressed through role loss. Elders must have a negotiable commodity to exchange as well as the flexibility to adjust to changes in the extended family. Maintaining continuity of the family in the face of disruptive threats poses a particular challenge for elders.     

Treatment of malaria in Ethiopian folk medicine

Key informant interviews of herbalists were conducted to document the traditional management of malaria in Ethiopia. The perceptions of the cause and symptoms of malaria, the use of plants, their preparation and administration were recorded. Interviews were performed in rural Butajira and Addis Ababa (the main city). The result showed that 33 (75%) of the interviewed healers treat malaria using herbal drugs. Sixteen plants were reported to have been used of which eight were used as a single remedy and the rest as composite remedies with other plants. The ethnopharmacological data generated in this study on antimalarial plants is useful for further evaluations of the traditional claims of antimalarial plants in Ethiopia.     

Prophylactic granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor decrease febrile neutropenia after chemotherapy in children with cancer: a meta-analysis of randomized controlled trials.

PURPOSE: To determine whether prophylactic hematopoietic colony-stimulating factors (CSFs) used in children with cancer reduce the rate of febrile neutropenia, hospitalization duration, documented infection rate, parenteral antibiotic duration, amphotericin B use, or infection-related mortality. METHODS: We included studies in this meta-analysis if their populations consisted of children, if there was randomization between CSFs and placebo or no therapy, if CSFs were administered prophylactically (before neutropenia or febrile neutropenia), and if chemotherapy treatments preceding CSFs and placebo or no therapy were identical. From 971 reviewed study articles, 16 were included. RESULTS: The mean rate of febrile neutropenia in the control arms was 57% (range, 39% to 100%). Using a random effects model, CSFs were associated with a reduction in febrile neutropenia, with a rate ratio of 0.80 (95% CI, 0.67 to 0.95; P =.01), and a decrease in hospitalization length, with a weighted mean difference of -1.9 days (95% CI, -2.7 to -1.1 days; P <.00001). CSF use was also associated with reduction in documented infections (rate ratio, 0.78; 95% CI, 0.62 to 0.97; P =.02) and reduction in amphotericin B use (rate ratio, 0.50; 95% CI, 0.28 to 0.87; P =.02). There was no difference in duration of parenteral antibiotic therapy (weighted mean difference, -4.3; 95% CI, -10.6 to 2.0 days; P =.2) or infection-related mortality (rate ratio, 1.02; 95% CI, 0.34 to 3.06; P =.97). CONCLUSION: CSFs were associated with a 20% reduction in febrile neutropenia and shorter duration of hospitalization; however, CSFs did not reduce infection-related mortality.