Guidance for using pilot studies to inform the design of intervention trials with continuous outcomes

Background: A pilot study can be an important step in the assessment of an intervention by providing information to design the future definitive trial. Pilot studies can be used to estimate the recruitment and retention rates and population variance and to provide preliminary evidence of efficacy potential. However, estimation is poor because pilot studies are small, so sensitivity analyses for the main trial's sample size calculations should be undertaken. Methods: We demonstrate how to carry out easy-to-perform sensitivity analysis for designing trials based on pilot data using an example. Furthermore, we introduce rules of thumb for the size of the pilot study so that the overall sample size, for both pilot and main trials, is minimized. Results: The example illustrates how sample size estimates for the main trial can alter dramatically by plausibly varying assumptions. Required sample size for 90% power varied from 392 to 692 depending on assumptions. Some scenarios were not feasible based on the pilot study recruitment and retention rates. Conclusion: Pilot studies can be used to help design the main trial, but caution should be exercised. We recommend the use of sensitivity analyses to assess the robustness of the design assumptions for a main trial

Validation of the NPL gravimetric hygrometer

The gravimetric hygrometer of the UK National Physical Laboratory (NPL) provides a first-principles realisation of mixing ratio - the most fundamental measure of the humidity of a gas. The operation of the NPL gravimetric hygrometer has been validated to demonstrate its satisfactory performance as a primary standard for humidity within the UK national measurement system. The measurement performance of the gravimetric hygrometer has been characterised for mixing ratios within the range 0.01 g kg to 155 g kg 4 (equivalent at atmospheric pressure to a dew-point range of -60 °C to +60 °C). The significant aspects of the measurement have been assessed in detail; these being the balances and weighing processes, the efficiency of collecting water and dry gas, and the effects of stray water in the instrument. Sources of systematic error have been identified and their effects quantified. Wherever possible, such errors have been eliminated or reduced. Elsewhere, numerical corrections have been evaluated and applied to the results of measurements. The overall uncertainty of measurement for the gravimetric hygrometer has been estimated by evaluating the uncertainties contributed by each aspect of the measurement, and combining these statistically to find the overall effect. The estimated uncertainty at a level of confidence of approximately 95% (a coverage factor of k=2) was found to range between 0.015 percent of value at the highest humidity considered, near 155 g kg 1, and 1.27 percent of value at the lower limit of 0.01 g kg1. The gravimetric hygrometer has been intercompared with the humidity generator which is the NFL standard for dew point, using nitrogen as the carrier gas in these measurements. For the conversion between values of dew point and mixing ratio, the uncertainties in the reference functions have been reviewed for the vapour pressure curve of water, and for the water vapour enhancement factor which accounts for the non-ideal behaviour of humid gases. A new calculation of the enhancement factor for nitrogen is presented. The uncertainties due to sampling were also evaluated. On average, the uncertainties due to the reference functions and those due to sampling were found to comparable with the uncertainty in the gravimetric measurements. Taking all these into account, the intercomparison measurements agreed to within the combined uncertainties of the two instruments

Precipitation and latent heating distributions from satellite passive microwave radiometry. Part I: improved method and uncertainties

A revised Bayesian algorithm for estimating surface rain rate, convective rain proportion, and latent heating profiles from satellite-borne passive microwave radiometer observations over ocean backgrounds is described. The algorithm searches a large database of cloud-radiative model simulations to find cloud profiles that are radiatively consistent with a given set of microwave radiance measurements. The properties of these radiatively consistent profiles are then composited to obtain best estimates of the observed properties. The revised algorithm is supported by an expanded and more physically consistent database of cloud-radiative model simulations. The algorithm also features a better quantification of the convective and nonconvective contributions to total rainfall, a new geographic database, and an improved representation of background radiances in rain-free regions. Bias and random error estimates are derived from applications of the algorithm to synthetic radiance data, based upon a subset of cloud-resolving model simulations, and from the Bayesian formulation itself. Synthetic rain-rate and latent heating estimates exhibit a trend of high (low) bias for low (high) retrieved values. The Bayesian estimates of random error are propagated to represent errors at coarser time and space resolutions, based upon applications of the algorithm to TRMM Microwave Imager (TMI) data. Errors in TMI instantaneous rain-rate estimates at 0.5°-resolution range from approximately 50% at 1 mm h−1 to 20% at 14 mm h−1. Errors in collocated spaceborne radar rain-rate estimates are roughly 50%–80% of the TMI errors at this resolution. The estimated algorithm random error in TMI rain rates at monthly, 2.5° resolution is relatively small (less than 6% at 5 mm day−1) in comparison with the random error resulting from infrequent satellite temporal sampling (8%–35% at the same rain rate). Percentage errors resulting from sampling decrease with increasing rain rate, and sampling errors in latent heating rates follow the same trend. Averaging over 3 months reduces sampling errors in rain rates to 6%–15% at 5 mm day−1, with proportionate reductions in latent heating sampling errors

The renormalization of the axial anomaly in dimensional regularization

The prescription for the $\gamma_5$-matrix within dimensional regularization in multiloop calculations is elaborated. The three-loop anomalous dimension of the singlet axial current is calculated.Comment: 11 pages, 1 figure available on request from the author, NIKHEF-H/92-1

Thermal compression of two-dimensional atomic hydrogen to quantum degeneracy

We describe experiments where 2D atomic hydrogen gas is compressed thermally at a small "cold spot" on the surface of superfluid helium and detected directly with electron-spin resonance. We reach surface densities up to 5e12 1/cm^2 at temperatures of approximately 100 mK corresponding to the maximum 2D phase-space density of about 1.5. By independent measurements of the surface density and its decay rate we make the first direct determination of the three-body recombination rate constant and get the value of 2e-25 cm^4/s for its upper bound, which is an order of magnitude smaller than previously reported experimental results.Comment: 4 pages, 4 postscript figures, bibliography (.bbl) file, submitted to PR

Altered frontal and insular functional connectivity as pivotal mechanisms for apathy in Alzheimer’s disease

Background: Apathy is a common and early symptom in Alzheimer’s disease (AD) and is linked to poorer prognosis. Theoretical interpretations of apathy implicate alterations of connections amongst fronto-striatal and limbic regions. Objective: To test the association between presence of apathy and patterns of brain functional connectivity in patients with clinically-established AD. Methods: Seventy AD patients were included. Thirty-five patients experienced apathy as defined by the screening question of the Neuropsychiatric Inventory, and thirty-five did not. All patients agreed to undergo an MRI protocol inclusive of resting-state acquisitions. The hemodynamic-dependent signal was extracted bilaterally from five regions of interest: ventromedial prefrontal cortices, anterior cingulate cortices, dorsolateral prefrontal cortices, insulae and amygdalae. t tests were run to compare connectivity maps of apathetic and non-apathetic patients. Age, education, Mini Mental State Examination score, gray matter volumes and gray matter fractions served as covariates. Results: At a pFWE < 0.05 threshold, apathetic patients had reduced connectivity between the left insula and right superior parietal cortex. Apathetic patients had also increased connectivity between the right dorsolateral prefrontal seed and the right superior parietal cortex. Patients with apathy were significantly more likely to experience other psychiatric symptoms. Conclusion: Our findings support a role of frontal and insular connections in coordinating value-based decisions in AD. Both down-regulation and maladaptive up-regulation mechanisms appear to be at play in these regions

Vicarious experience affects patients' treatment preferences for depression

Purpose: Depression is common in primary care but often under-treated. Personal experiences with depression can affect adherence to therapy, but the effect of vicarious experience is unstudied. We sought to evaluate the association between a patient's vicarious experiences with depression (those of friends or family) and treatment preferences for depressive symptoms. Methods: We sampled 1054 English and/or Spanish speaking adult subjects from July through December 2008, randomly selected from the 2008 California Behavioral Risk Factor Survey System, regarding depressive symptoms and treatment preferences. We then constructed a unidimensional scale using item analysis that reflects attitudes about antidepressant pharmacotherapy. This became the dependent variable in linear regression analyses to examine the association between vicarious experiences and treatment preferences for depressive symptoms. Results: Our sample was 68% female, 91% white, and 13% Hispanic. Age ranged from 18-94 years. Mean PHQ-9 score was 4.3; 14.5% of respondents had a PHQ-9 score >9.0, consistent with active depressive symptoms. Analyses controlling for current depression symptoms and socio-demographic factors found that in patients both with (coefficient 1.08, p = 0.03) and without (coefficient 0.77, p = 0.03) a personal history of depression, having a vicarious experience (family and friend, respectively) with depression is associated with a more favorable attitude towards antidepressant medications. Conclusions: Patients with vicarious experiences of depression express more acceptance of pharmacotherapy. Conversely, patients lacking vicarious experiences of depression have more negative attitudes towards antidepressants. When discussing treatment with patients, clinicians should inquire about vicarious experiences of depression. This information may identify patients at greater risk for non-adherence and lead to more tailored patient-specific education about treatment

Background Thermal Contributions in Testing the Unruh Effect

We consider inertial and accelerated Unruh-DeWitt detectors moving in a background thermal bath and calculate their excitation rates. It is shown that for fast moving detectors such a thermal bath does not affect substantially the excitation probability. Our results are discussed in connection with a possible proposal of testing the Unruh effect in high energy particle accelerators.Comment: 13 pages, (REVTEX 3.0), 3 figures available upon reques

Bohmian Mechanics and Quantum Information

Many recent results suggest that quantum theory is about information, and that quantum theory is best understood as arising from principles concerning information and information processing. At the same time, by far the simplest version of quantum mechanics, Bohmian mechanics, is concerned, not with information but with the behavior of an objective microscopic reality given by particles and their positions. What I would like to do here is to examine whether, and to what extent, the importance of information, observation, and the like in quantum theory can be understood from a Bohmian perspective. I would like to explore the hypothesis that the idea that information plays a special role in physics naturally emerges in a Bohmian universe.Comment: 25 pages, 2 figure

Integer Vector Addition Systems with States

This paper studies reachability, coverability and inclusion problems for Integer Vector Addition Systems with States (ZVASS) and extensions and restrictions thereof. A ZVASS comprises a finite-state controller with a finite number of counters ranging over the integers. Although it is folklore that reachability in ZVASS is NP-complete, it turns out that despite their naturalness, from a complexity point of view this class has received little attention in the literature. We fill this gap by providing an in-depth analysis of the computational complexity of the aforementioned decision problems. Most interestingly, it turns out that while the addition of reset operations to ordinary VASS leads to undecidability and Ackermann-hardness of reachability and coverability, respectively, they can be added to ZVASS while retaining NP-completness of both coverability and reachability.Comment: 17 pages, 2 figure