Efficiently Identifying Failures using Quantitative Tests, Matrix-Pooling and the EM-Algorithm

Pooled-testing methods can greatly reduce the number of tests needed to identify failures in a collection of samples. Existing methodology has focused primarily on binary tests, but there is a clear need for improved efficiency when using expensive quantitative tests, such as tests for HIV viral load in resource-limited settings. We propose a matrix-pooling method which, based on pooled-test results, uses the EM algorithm to identify individual samples most likely to be failures. Two hundred datasets for each of a wide range of failure prevalence were simulated to test the method. When the measurement of interest was normally distributed, at a failure prevalence level of 15.6% the EM method yielded a 47.3% reduction in the number of tests needed to identify failures (as compared to testing each specimen individually). These results are somewhat better than the reduction gained by using the Simple Search method (44.9%) previously published by May et al. (2010). However, the EM procedure was able to identify failures in just 2.6 testing rounds, on average, as compared to an average of 19.2 testing rounds required by Simple Search. In settings where the turn-around time for testing services is significant, the reduction in testing rounds provided by the EM method is substantial. Unfortunately the EM method does not perform as well when the measurements of interest are highly skewed, as is often the case with viral load concentrations

Adaptive Non-Inferiority Margins under Observable Non-Constancy

A central assumption in the design and conduct of non-inferiority trials is that the active-control therapy will have the same degree of effectiveness in the planned non-inferiority trial as it had in the prior placebo-controlled trials used to define the non-inferiority margin. This is referred to as the `constancy\u27 assumption. If the constancy assumption fails, the chosen non-inferiority margin is not valid and the study runs the risk of approving an inferior product or failing to approve a beneficial product. The constancy assumption cannot be validated in a trial without a placebo arm, and it is unlikely ever to be met completely. However, it is often the case that there exist strong, measurable predictors of constancy, such as dosing and adherence, and such predictors can be used to identify situations where the constancy assumption will likely fail. Here we propose a method for using measurable predictors of active-control effectiveness to specify non-inferiority margins targeted to the planned study population, and further use these predictors to adapt the non-inferiority margin at the end of the study. Population-specific margins can help avoid violations of the constancy assumption, and adaptive margins can help adjust for violations that will inevitably occur in real clinical trials, while at the same time maintain pre-specified levels of type I error and power

The impact of four common lumbar spine diagnoses upon overall health status

Background Context: The SF-36 health survey has been shown to be a valid instrument when used to measure the self-reported physical and mental health of patients. The impact of lumbar spinal disorders can be assessed as the difference between the SF-36 scale scores and age-and-gender specific population norms. Purpose: To establish the impact upon the self-reported health status of patients with one of four common lumbar spinal diagnoses. Study Design: A cross-sectional, observational assessment of the health status of spine patients. Methods: Data from patients presenting to the participating centers of the National Spine Network with low back pain and/or leg pain, was collected prospectively using the Health Status Questionnaire 2.0. A database search identified patients with either herniated nucleus pulposus with radicular pain (HNP), lumbar spinal stenosis without deformity (SPS), degenerative spondylolisthesis (DS), and painful disc degeneration/spondylosis (DDD). The mean SF-36 scale scores were generated for each of the diagnostic groups. The impact of these diagnoses on health status was determined as the calculated difference from the age-and-gender specific population norms for each of the eight health scale scores. These scores, usually negative in this population, represent how far below normal these patients are. The analysis was stratified according to the age of the patients (\u3c40 yrs, 40-60 yrs, \u3e60 yrs). Analysis of variance and pair-wise comparison with Bonferroni correction were used to assess the significance of differences across diagnosis and age groups. Results: Data from a total of 4,442 patients was available for this study. All four diagnostic groups had large, negative impact scores for the eight general health scales with the greatest impact upon the three scales that best measure physical health. The greatest impact on these physical health scales (physical functioning, role-physical, and bodily pain) was seen in the HNP diagnostic group. The younger age groups (\u3c40 yrs and 40-60 yrs) had the greatest physical impairment when compared to the age-and-gender specific population norms. Analysis of variance showed a significant relationship between diagnosis and SF-36 scores, and between age groups and SF-36 scores. Conclusions: All four lumbar spine disorders have a significant negative impact on all eight of the SF-36 scales. The greatest negative impact was seen in those scales that measure physical health (RP, PF, and BP). The HNP diagnostic group experienced a significantly greater impact upon these three scales. This diagnostic group had the youngest patients, whose baseline physical functional status would be expected to be the most optimal. When we stratified by age in all the diagnostic groups, the greatest negative impact scores for physical health were seen in the \u3c 40 yrs and 40-60 yrs age groups. These patients were also more likely to perceive their health as poor, experience decreased energy, and have more social impairment when compared to their age/gender norms

Surgical versus nonsurgical therapy for lumbar spinal stenosis.

BACKGROUND: Surgery for spinal stenosis is widely performed, but its effectiveness as compared with nonsurgical treatment has not been shown in controlled trials. METHODS: Surgical candidates with a history of at least 12 weeks of symptoms and spinal stenosis without spondylolisthesis (as confirmed on imaging) were enrolled in either a randomized cohort or an observational cohort at 13 U.S. spine clinics. Treatment was decompressive surgery or usual nonsurgical care. The primary outcomes were measures of bodily pain and physical function on the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36) and the modified Oswestry Disability Index at 6 weeks, 3 months, 6 months, and 1 and 2 years. RESULTS: A total of 289 patients were enrolled in the randomized cohort, and 365 patients were enrolled in the observational cohort. At 2 years, 67% of patients who were randomly assigned to surgery had undergone surgery, whereas 43% of those who were randomly assigned to receive nonsurgical care had also undergone surgery. Despite the high level of nonadherence, the intention-to-treat analysis of the randomized cohort showed a significant treatment effect favoring surgery on the SF-36 scale for bodily pain, with a mean difference in change from baseline of 7.8 (95% confidence interval, 1.5 to 14.1); however, there was no significant difference in scores on physical function or on the Oswestry Disability Index. The as-treated analysis, which combined both cohorts and was adjusted for potential confounders, showed a significant advantage for surgery by 3 months for all primary outcomes; these changes remained significant at 2 years. CONCLUSIONS: In the combined as-treated analysis, patients who underwent surgery showed significantly more improvement in all primary outcomes than did patients who were treated nonsurgically. (ClinicalTrials.gov number, NCT00000411 [ClinicalTrials.gov].)

HIV prevention trial design in an era of effective pre-exposure prophylaxis.

CAPRISA, 2017.Abstract available in pdf

Surgical versus nonsurgical treatment for lumbar degenerative spondylolisthesis.

BACKGROUND: Management of degenerative spondylolisthesis with spinal stenosis is controversial. Surgery is widely used, but its effectiveness in comparison with that of nonsurgical treatment has not been demonstrated in controlled trials. METHODS: Surgical candidates from 13 centers in 11 U.S. states who had at least 12 weeks of symptoms and image-confirmed degenerative spondylolisthesis were offered enrollment in a randomized cohort or an observational cohort. Treatment was standard decompressive laminectomy (with or without fusion) or usual nonsurgical care. The primary outcome measures were the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36) bodily pain and physical function scores (100-point scales, with higher scores indicating less severe symptoms) and the modified Oswestry Disability Index (100-point scale, with lower scores indicating less severe symptoms) at 6 weeks, 3 months, 6 months, 1 year, and 2 years. RESULTS: We enrolled 304 patients in the randomized cohort and 303 in the observational cohort. The baseline characteristics of the two cohorts were similar. The one-year crossover rates were high in the randomized cohort (approximately 40% in each direction) but moderate in the observational cohort (17% crossover to surgery and 3% crossover to nonsurgical care). The intention-to-treat analysis for the randomized cohort showed no statistically significant effects for the primary outcomes. The as-treated analysis for both cohorts combined showed a significant advantage for surgery at 3 months that increased at 1 year and diminished only slightly at 2 years. The treatment effects at 2 years were 18.1 for bodily pain (95% confidence interval [CI], 14.5 to 21.7), 18.3 for physical function (95% CI, 14.6 to 21.9), and -16.7 for the Oswestry Disability Index (95% CI, -19.5 to -13.9). There was little evidence of harm from either treatment. CONCLUSIONS: In nonrandomized as-treated comparisons with careful control for potentially confounding baseline factors, patients with degenerative spondylolisthesis and spinal stenosis treated surgically showed substantially greater improvement in pain and function during a period of 2 years than patients treated nonsurgically. (ClinicalTrials.gov number, NCT00000409 [ClinicalTrials.gov].)

Safety, tolerability, pharmacokinetics, and immunological activity ...

This phase 1 study showed the feasibility of combining anti-HIV bnAbs targeting different sites on the HIV envelope in people living without HIV. It also showed that the dual-antibody and triple-antibody combinations were as effective as the individual antibodies at neutralisation, thus justifying a combination approach going forward for additional monoclonal antibody studies for HIV prevention. The fact that modelling predicted the combination neutralisation titre on the basis of the single antibody titres will be valuable for future trial design of different antibody combinations