A practical comparison of group-sequential and adaptive designs

Sequential methods provide a formal framework by which clinical trial data can be monitored as they accumulate. The results from interim analyses can be used either to modify the design of the remainder of the trial or to stop the trial as soon as sufficient evidence of either the presence or absence of a treatment effect is available. The circumstances under which the trial will be stopped with a claim of superiority for the experimental treatment, must, however, be determined in advance so as to control the overall type I error rate. One approach to calculating the stopping rule is the group-sequential method. A relatively recent alternative to group-sequential approaches is the adaptive design method. This latter approach provides considerable flexibility in changes to the design of a clinical trial at an interim point. However, a criticism is that the method by which evidence from different parts of the trial is combined means that a final comparison of treatments is not based on a sufficient statistic for the treatment difference, suggesting that the method may lack power. The aim of this paper is to compare two adaptive design approaches with the group-sequential approach. We first compare the form of the stopping boundaries obtained using the different methods. We then focus on a comparison of the power of the different trials when they are designed so as to be as similar as possible. We conclude that all methods acceptably control type I error rate and power when the sample size is modified based on a variance estimate, provided no interim analysis is so small that the asymptotic properties of the test statistic no longer hold. In the latter case, the group-sequential approach is to be preferred. Provided that asymptotic assumptions hold, the adaptive design approaches control the type I error rate even if the sample size is adjusted on the basis of an estimate of the treatment effect, showing that the adaptive designs allow more modifications than the group-sequential method.     

Effects of occupational exposure to organophosphate pesticides on nerve and neuromuscular function

This study aimed to investigate whether occupational exposure to organophosphate (OP) pesticides caused neurophysiological abnormalities. Thirty farmers who regularly spray OP pesticides and 30 fishermen (controls), living close by but not involved in pesticide spraying, were evaluated during and between cultivation seasons. The farmers had higher erythrocyte acetylcholinesterase levels than the controls during (P = 0.06) and between cultivation seasons (P = 0.09). During the cultivation season, there was a significant reduction in erythrocyte acetylcholinesterase activity in both groups (P < 0.01). Significant differences between the farmers and controls were found in sensory conduction velocity (P = 0.04) and motor conduction velocity (P = 0.04) between cultivation seasons. Sensory conduction velocity was reduced significantly in farmers (P < 0.01) and in controls (P = 0.04) during the cultivation season. Effects of OP poisoning were seen both in farmers and in controls, who had no history of spray activities. Evidence of sensory dysfunction after acute exposure and sensory and motor impairment after long-term low-level exposure to OP was seen.     

Enhanced cerebral but not peripheral angiogenesis in the Goto-Kakizaki model of type 2 diabetes involves VEGF and peroxynitrite signaling

We previously reported enhanced cerebrovascular remodeling and arteriogenesis in experimental type 2 diabetes. This study tested the hypotheses that 1) cerebral but not peripheral angiogenesis is increased in a spatial manner and 2) peroxynitrite orchestrates vascular endothelial growth factor (VEGF)-mediated brain angiogenesis in diabetes. Stereology of brain, eye, and skeletal muscle microvasculature was evaluated in control and diabetic rats using three-dimensional images. Migration and tube formation properties of brain microvascular endothelial cells (BMECs) were analyzed as markers of angiogenesis. Vascular density, volume, and surface area were progressively increased from rostral to caudal sections in both the cerebral cortex and striatum in diabetic rats. Unperfused new vessels were more prominent and the pericyte-to-endothelial cell ratio was decreased in diabetes. Vascularization was greater in the retina but lower in the peripheral circulation. VEGF and nitrotyrosine levels were higher in cerebral microvessels of diabetic animals. Migratory and tube formation properties were enhanced in BMECs from diabetic rats, which also expressed high levels of basal VEGF, nitrotyrosine, and membrane-type (MT1) matrix metalloprotease (MMP). VEGF-neutralizing antibody and inhibitors of peroxynitrite, src kinase, or MMP blocked the migration. Diabetes increases and spatially regulates cerebral neovascularization. Increased VEGF-dependent angiogenic function in BMECs is mediated by peroxynitrite and involves c-src and MT1-MMP activation.     

Diagnostic performance of quantitative kappa and lambda free light chain assays in clinical practice

BACKGROUND: The quantitative assay for free light chains (FLCs) is a recently introduced commercial test reported to be sensitive and specific for detecting FLC diseases such as primary systemic amyloidosis (AL), light chain deposition disease (LCDD), nonsecretory multiple myeloma (NSMM), and light chain multiple myeloma. We evaluated its diagnostic performance in clinical practice. METHODS: All FLC clinical test results generated in 2003 were abstracted from the Laboratory Information System. Diagnoses were obtained from the Dysproteinemia database and the patient medical history. RESULTS: In 2003, we received samples for FLC assays from 1020 Mayo Clinic patients. The majority of these patients (88%) had bone marrow-derived monoclonal plasma cell disorders (PCDs). The 121 patients who did not have monoclonal gammopathy all had FLC kappa/lambda ratios within the range of values obtained for a reference population in our laboratory. Among the patients with monoclonal gammopathies were patients with multiple myeloma (330), AL (269), monoclonal gammopathy of undetermined significance (114), smoldering multiple myeloma (72), plasmacytoma (22), NSMM (20), macroglobulinemia (9), LCDD (7), and a variety of other PCDs. Among the 110 AL patients who had not been previously treated and who had a FLC assay performed within 120 days of diagnosis, the FLC kappa/lambda ratio was positive in 91% compared with 69% for serum immunofixation electrophoresis (IFE) and 83% for urine IFE. The combination of serum IFE and serum FLC assay detected an abnormal result in 99% (109 of 110) of patients with AL. CONCLUSION: The performance of the FLC assay in this analysis of clinical laboratory data is consistent with results from published retrospective validation studies.     

Diagnostic Utility of Complement Serology for Atypical Hemolytic Uremic Syndrome

Objective

To investigate the clinical utility of a 9-analyte complement serology panel (COMS) covering complement function (CH50 and AH50), components (C3, C4), factor B (CFB), factor H, and activation markers (C4d, Bb, and soluble membrane attack complex) for the diagnosis of atypical hemolytic uremic syndrome (aHUS).

Immune evaluation and vaccine responses in Down syndrome: evidence of immunodeficiency?

Background

Patients with Down syndrome (DS) appear to be at a greater risk for serious infections, but it is unclear whether this is due to anatomic variations or intrinsic immune defects.

Objective

We assessed a cohort of pediatric subjects with DS to determine if immunological abnormalities indeed account for the excess infections.

Methods

We performed quantitative assessment of T-independent (type 2 - pneumococcal polysaccharide vaccine) and T-dependent Ab responses (with inactivated seasonal influenza vaccine) along with numerical quantitation of lymphocyte subpopulations and thymic output in a random population sample of children with DS (cases) along with family-matched sibling or community controls.

Results

Median serum IgG levels were significantly higher in cases (1090 mg/dL) as compared with controls (808 mg/dL, P = 0.02). Cases had significantly lower median CD4 T cell counts than the controls (636 cells/μL, P = 0.01). Cases had reduced CD19 B cell counts and CD19% than the controls (P = 0.009 and 0.006 respectively). Cases also showed decreased total memory (CD19+CD27+, P = 0.002) and class-switched memory (CD19+CD27+IgM−IgD−, P = 0.004) B cells.The median CD4 recent thymic emigrant (RTE) in females and males cases was lower than controls (P = 0.007 and 0.07 respectively). Cases had a lower median T cell receptor excision circle (TREC) count of 2556 as compared to the controls count of 5216, P < 0.006 although both the cases and controls were within the established reference range. There were no differences in the percentage of cases and controls who responded to inactivated influenza vaccine, but the response to polysaccharide pneumococcal vaccine was suboptimal in cases.

Conclusions

Our study suggests that there are subtle abnormalities in both humoral and cellular arms of the immune response in children with DS as compared to the control subjects.     

Exploration of High- and Low-Frequency Options for Subperception Spinal Cord Stimulation Using Neural Dosing Parameter Relationships: The HALO Study

ObjectivesSubperception spinal cord stimulation (SCS) is described mostly utilizing waveforms that require high energy. However, the necessity of these waveforms for effective subperception has not been established. We aimed to explore whether effective subperception pain relief can be achieved using frequencies below 1 kHz.Materials and MethodsThirty chronic pain patients implanted with SCS were enrolled as part of a multicenter, real-world, consecutive, observational case series. An effective stimulation location was determined using a novel electric field shape designed to preferentially modulate dorsal horn elements. Subsequently, programs at lower frequencies (600, 400, 200, 100, 50, and 10 Hz) were provided with pulse-width and amplitude adjusted to optimize response.ResultsAll tested frequencies (1 kHz down to 10 Hz) provided effective subperception relief, yielding a mean of 66–72% reduction in back, leg, and overall pain. It was found that to maintain analgesia, as frequency was decreased, the electrical or “neural” dose had to be adjusted according to parameter relationships described herein. With the reduction of frequency, we observed a net reduction of charge-per-second, which enabled energy savings of 74% (200 Hz) and 97% (10 Hz) relative to 1 kHz. Furthermore, pain reduction was sustained out to one year, with 85% of patients reporting a preference for frequencies of 400 Hz or below.ConclusionsWe have derived an electric field configuration and, along with previous learnings in the kHz range, a set of neural dosing parameter relationships (10–10,000 Hz), which enable the expansion of effective subperception SCS to low frequency and achieve major energy savings.     

Educating health science students about disability: Teachers’ perspectives on curricular gaps

BackgroundPeople living with disabilities are significantly more likely than their peers to find health professionals’ skills and facilities inadequate. The 66th World Health Assembly called for better health care for people with disabilities including more inclusive health services and a stronger focus on professional training.ObjectiveTo explore how teachers at a New Zealand university perceived the need, approaches, and systemic challenges to enhance disability education for health professionals in training.MethodsQualitative analysis of interviews with 11 key informants teaching in population health, medicine, nursing, pharmacy, and optometry training programmes. Transcribed interview recordings were analysed using a general inductive approach.ResultsThe participants described a range of teaching approaches that they used to increase disability awareness among their students. However, these were largely ad hoc individually driven initiatives reflecting personal interests. Participants identified a critical need to develop and implement a systematic, integrated approach to enhance disability education particularly from a social justice perspective among students in health disciplines. Engaging people with lived experience of disability in teaching and course design, and senior administrative commitment were identified as necessary to address current gaps in education.ConclusionsIn order to develop a health professional workforce competent to respond to the needs of people with disabilities, greater attention is required at a strategic level to enhance the profile of disability education in health curricula. Meaningful engagement of people with disability and senior leadership commitment are critical components that can enable effective progression of this agenda.