Information-adaptive clinical trials: a selective recruitment design

We propose a novel adaptive design for clinical trials with time-to-event outcomes and covariates (which may consist of or include biomarkers). Our method is based on the expected entropy of the posterior distribution of a proportional hazards model. The expected entropy is evaluated as a function of a patient's covariates, and the information gained due to a patient is defined as the decrease in the corresponding entropy. Candidate patients are only recruited onto the trial if they are likely to provide sufficient information. Patients with covariates that are deemed uninformative are filtered out. A special case is where all patients are recruited, and we determine the optimal treatment arm allocation. This adaptive design has the advantage of potentially elucidating the relationship between covariates, treatments, and survival probabilities using fewer patients, albeit at the cost of rejecting some candidates. We assess the performance of our adaptive design using data from the German Breast Cancer Study group and numerical simulations of a biomarker validation trial

Vascular Plants of the Truelove Inlet Region, Devon Island

Ninety-three species of vascular plants are recorded from a 16 sq. mile coastal lowland on the northern coast of Devon Island, Northwest Territories. The following taxa are apparently new records for Devon Island: Cystopteris fragilis, Woodsia alpina, Equisetum variegatum, Poa alpigena, Carex amblyorhyncha, Draba oblongata, Saxifraga tenuis, Epilobium arcticum, Hippuris vulgaris, Pedicularis lanata, Puccinellia vaginata var. paradoxa. These additions bring the total known flora of Devon Island to 115 species. The Truelove flora is part of the High Arctic biogeographic element of the Canadian Arctic Archipelago. However, a distinct element of species of more southerly distribution is present probably due to the moderating influence of the lowland environment

Information-adaptive clinical trials with selective recruitment and binary outcomes

Selective recruitment designs preferentially recruit individuals that are estimated to be statistically informative onto a clinical trial. Individuals that are expected to contribute less information have a lower probability of recruitment. Furthermore, in an information-adaptive design recruits are allocated to treatment arms in a manner that maximises information gain. The informativeness of an individual depends on their covariate (or biomarker) values and how information is defined is a critical element of information-adaptive designs. In this paper we define and evaluate four different methods for quantifying statistical information. Using both experimental data and numerical simulations we show that selective recruitment designs can offer a substantial increase in statistical power compared to randomised designs. In trials without selective recruitment we find that allocating individuals to treatment arms according to information-adaptive protocols also leads to an increase in statistical power. Consequently, selective recruitment designs can potentially achieve successful trials using fewer recruits thereby offering economic and ethical advantages

An Analysis of the Long-Term Salinity Patterns in the Louisiana Coastal Zone

Saltwater intrusion is believed to be one of the greatest threats to Louisiana\u27s fishery and wildlife resources. The Louisiana Department of Wildlife and Fisheries has maintained salinity recording stations throughout the state\u27s coastal marshes since the 1960\u27s. We applied several different analytical approaches to the salinity data from 17 stations to determine whether this data base could be used to detect and quantity long-term salinity trends in coastal Louisiana. We did not detect a large-scale, consistent trend over time in coastal salinities across the state. Problems that hindered the detection of long-term trends included short periods of record and the placement of the recording stations in salt and brackish marsh areas, where we would not expect to find great changes in salinity. For the data to be useful in monitoring salinity trends in coastal marshes, especially with respect to saltwater intrusion, stations should be added in fresh and intermediate marshes. In addition, the relationships our study revealed between short- and long-term data indicate that records covering less than a decade are insufficient to denote long-term salinity changes, barring some major modification of the hydrologic regime

Predicting The Effect of Moisture Content On The Flexural Properties of Douglas-Fir Dimension Lumber

Current procedures for adjusting estimates of the mechanical properties of lumber for changes in moisture content are based on trends in the observed means. The present study was initiated to develop analytical procedures for adjusting estimates of the flexural properties of 2-inch-thick Douglas-fir dimension lumber that would be applicable to all levels of the flexural properties. Equations are derived for adjusting modulus of rupture (MOR), modulus of elasticity (MOE), moment capacity (RS = MOR x section modulus), and flexural stiffness (EI = MOEX moment of inertia) for changes in moisture content. The best of these equations are found to be significantly more accurate than current procedures for adjusting estimates of strength properties such as MOR and RS. Because MOE and EI are less affected by changes in moisture content, most of the equations work well for these properties

The WID-CIN test identifies women with, and at risk of, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer

BACKGROUND: Cervical screening is transitioning from primary cytology to primary human papillomavirus (HPV) testing. HPV testing is highly sensitive but there is currently no high-specificity triage method for colposcopy referral to detect cervical intraepithelial neoplasia grade 3 or above (CIN3+) in women positive for high-risk (hr) HPV subtypes. An objective, automatable test that could accurately perform triage, independently of sample heterogeneity and age, is urgently required. METHODS: We analyzed DNA methylation at ~850,000 CpG sites across the genome in a total of 1254 cervical liquid-based cytology (LBC) samples from cases of screen-detected histologically verified CIN1-3+ (98% hrHPV-positive) and population-based control women free from any cervical disease (100% hrHPV-positive). Samples were provided by a state-of-the-art population-based cohort biobank and consisted of (i) a discovery set of 170 CIN3+ cases and 202 hrHPV-positive/cytology-negative controls; (ii) a diagnostic validation set of 87 CIN3+, 90 CIN2, 166 CIN1, and 111 hrHPV-positive/cytology-negative controls; and (iii) a predictive validation set of 428 cytology-negative samples (418 hrHPV-positive) of which 210 were diagnosed with CIN3+ in the upcoming 1-4 years and 218 remained disease-free. RESULTS: We developed the WID-CIN (Women's cancer risk IDentification-Cervical Intraepithelial Neoplasia) test, a DNA methylation signature consisting of 5000 CpG sites. The receiver operating characteristic area under the curve (AUC) in the independent diagnostic validation set was 0.92 (95% CI 0.88-0.96). At 75% specificity (≤CIN1), the overall sensitivity to detect CIN3+ is 89.7% (83.3-96.1) in all and 92.7% (85.9-99.6) and 65.6% (49.2-82.1) in women aged ≥30 and <30. In hrHPV-positive/cytology-negative samples in the predictive validation set, the WID-CIN detected 54.8% (48.0-61.5) cases developing 1-4 years after sample donation in all ages or 56.9% (47.6-66.2) and 53.5% (43.7-63.2) in ≥30 and <30-year-old women, at a specificity of 75%. CONCLUSIONS: The WID-CIN test identifies the vast majority of hrHPV-positive women with current CIN3+ lesions. In the absence of cytologic abnormalities, a positive WID-CIN test result is likely to indicate a significantly increased risk of developing CIN3+ in the near future