Randomized trials, generalizability, and meta-analysis: Graphical insights for binary outcomes

BACKGROUND: Randomized trials stochastically answer the question. "What would be the effect of treatment on outcome if one turned back the clock and switched treatments in the given population?" Generalizations to other subjects are reliable only if the particular trial is performed on a random sample of the target population. By considering an unobserved binary variable, we graphically investigate how randomized trials can also stochastically answer the question, "What would be the effect of treatment on outcome in a population with a possibly different distribution of an unobserved binary baseline variable that does not interact with treatment in its effect on outcome?" METHOD: For three different outcome measures, absolute difference (DIF), relative risk (RR), and odds ratio (OR), we constructed a modified BK-Plot under the assumption that treatment has the same effect on outcome if either all or no subjects had a given level of the unobserved binary variable. (A BK-Plot shows the effect of an unobserved binary covariate on a binary outcome in two treatment groups; it was originally developed to explain Simpsons's paradox.) RESULTS: For DIF and RR, but not OR, the BK-Plot shows that the estimated treatment effect is invariant to the fraction of subjects with an unobserved binary variable at a given level. CONCLUSION: The BK-Plot provides a simple method to understand generalizability in randomized trials. Meta-analyses of randomized trials with a binary outcome that are based on DIF or RR, but not OR, will avoid bias from an unobserved covariate that does not interact with treatment in its effect on outcome

Determining Sex in Golden Eagle (AQUILA CHRYSAETOS) Nestling

Incorporating sex ratios of nestlings into population viability studies increases knowledge of overall health of endangered populations. Currently, a reliable non-invasive method to identify the sex of golden eagle nestlings is not available; however, claims are commonly made based on morphology. Ten biometric measurements from 43 Scottish golden eagles aged 2–7.5 weeks were assessed to see if sex could actually be determined using this non-invasive methodology. Sex was confirmed via molecular analysis of blood samples. Discrete and principal component analyses of the different biometrics could not correctly determine individual nestling sex. Therefore, despite being more invasive, molecular sexing remains the recommended tool of choice for accurate sex identification of Scottish golden eagle nestlings younger than 7.5 weeks of age. This has important implications for golden eagle field studies where empirical morphological measurements are frequently and typically taken, but we have shown are not reliable in determining the sex of such young nestlings

Quitting patient care and career break intentions among general practitioners in South West England: findings of a census survey of general practitioners

Objective: Given recent concerns regarding general practitioner (GP) workforce capacity, we aimed to describe GPs’ career intentions, especially those which might impact on GP workforce availability over the next 5 years. Design: Census survey, conducted between April and June 2016 using postal and online responses , of all GPs on the National Health Service performers list and eligible to practise in primary care. Two reminders were used as necessary. Setting: South West England (population 3.5  million), a region with low overall socioeconomic deprivation. Participants: Eligible GPs were 2248 out of 3370 (67 % response rate). Main outcome measures: Reported likelihood of permanently leaving or reducing hours spent in direct patient care or of taking a career break within the next 5 years and present morale weighted for non-response. Results: Responders included 217 7 GPs engaged in patient care. Of these, 863 (37% weighted, 95%  CI 35 % to 39 %) reported a high likelihood of quitting direct patient care within the next 5 years. Overall, 1535 (70% weighted, 95%  CI 68 % to 72 %) respondents reported a career intention that would negatively impact GP workforce capacity over the next 5 years, through permanently leaving or reducing hours spent in direct patient care, or through taking a career break. GP age was an important predictor of career intentions; sharp increases in the proportion of GPs intending to quit patient care were evident from 52 years. Only 305 (14% weighted, 95%  CI 13 % to 16 %) reported high morale, while 1195 ( 54 % weighted, 95%  CI 52 % to 56 %) reported low morale. Low morale was particularly common among GP partners. Current morale strongly predicted GPs’ career intentions; those with very low morale were particularly likely to report intentions to quit patient care or to take a career break. Conclusions: A substantial majority of GPs in South West England report low morale. Many are considering career intentions which, if implemented, would adversely impact GP workforce capacity within a short time period. Study registration: NIHR HS&DR - 14/196/02, UKCRN ID 20700

Goodness-of-Fit Tests for Symmetric Stable Distributions -- Empirical Characteristic Function Approach

We consider goodness-of-fit tests of symmetric stable distributions based on weighted integrals of the squared distance between the empirical characteristic function of the standardized data and the characteristic function of the standard symmetric stable distribution with the characteristic exponent $\alpha$ estimated from the data. We treat $\alpha$ as an unknown parameter, but for theoretical simplicity we also consider the case that $\alpha$ is fixed. For estimation of parameters and the standardization of data we use maximum likelihood estimator (MLE) and an equivariant integrated squared error estimator (EISE) which minimizes the weighted integral. We derive the asymptotic covariance function of the characteristic function process with parameters estimated by MLE and EISE. For the case of MLE, the eigenvalues of the covariance function are numerically evaluated and asymptotic distribution of the test statistic is obtained using complex integration. Simulation studies show that the asymptotic distribution of the test statistics is very accurate. We also present a formula of the asymptotic covariance function of the characteristic function process with parameters estimated by an efficient estimator for general distributions

The Pioneer Anomaly

Radio-metric Doppler tracking data received from the Pioneer 10 and 11 spacecraft from heliocentric distances of 20-70 AU has consistently indicated the presence of a small, anomalous, blue-shifted frequency drift uniformly changing with a rate of ~6 x 10^{-9} Hz/s. Ultimately, the drift was interpreted as a constant sunward deceleration of each particular spacecraft at the level of a_P = (8.74 +/- 1.33) x 10^{-10} m/s^2. This apparent violation of the Newton's gravitational inverse-square law has become known as the Pioneer anomaly; the nature of this anomaly remains unexplained. In this review, we summarize the current knowledge of the physical properties of the anomaly and the conditions that led to its detection and characterization. We review various mechanisms proposed to explain the anomaly and discuss the current state of efforts to determine its nature. A comprehensive new investigation of the anomalous behavior of the two Pioneers has begun recently. The new efforts rely on the much-extended set of radio-metric Doppler data for both spacecraft in conjunction with the newly available complete record of their telemetry files and a large archive of original project documentation. As the new study is yet to report its findings, this review provides the necessary background for the new results to appear in the near future. In particular, we provide a significant amount of information on the design, operations and behavior of the two Pioneers during their entire missions, including descriptions of various data formats and techniques used for their navigation and radio-science data analysis. As most of this information was recovered relatively recently, it was not used in the previous studies of the Pioneer anomaly, but it is critical for the new investigation.Comment: 165 pages, 40 figures, 16 tables; accepted for publication in Living Reviews in Relativit

Using observational data to estimate an upper bound on the reduction in cancer mortality due to periodic screening

BACKGROUND: Because randomized cancer screening trials are very expensive, observational cancer screening studies can play an important role in the early phases of screening evaluation. Periodic screening evaluation (PSE) is a methodology for estimating the reduction in population cancer mortality from data on subjects who receive regularly scheduled screens. Although PSE does not require assumptions about natural history of cancer it requires other assumptions, particularly progressive detection – the assumption that once a cancer is detected by a screening test, it will always be detected by the screening test. METHODS: We formulate a simple version of PSE and show that it leads to an upper bound on screening efficacy if the progressive detection assumption does not hold (and any effect of birth cohort is minimal) To determine if the upper bound is reasonable, for three randomized screening trials, we compared PSE estimates based only on screened subjects with PSE estimates based on all subjects. RESULTS: In the three randomized screening trials, PSE estimates based on screened subjects gave fairly close results to PSE estimates based on all subjects. CONCLUSION: PSE has promise for obtaining an upper bound on the reduction in population cancer mortality rates based on observational screening data. If the upper bound estimate is found to be small and any birth cohort effects are likely minimal, then a definitive randomized trial would not be warranted

Real-world practice level data analysis confirms link between variability within Blood Glucose Monitoring Strip (BGMS) and glycosylated haemoglobin (HbA1c) in Type 1 Diabetes.

AIMS/HYPOTHESIS: Our aim was to quantify the impact of Blood Glucose Monitoring Strips variability (BGMSV) at GP practice level on the variability of reported glycated haemoglobin (HbA1cV) levels. METHODS: Overall GP Practice BGMSV and HbA1cV were calculated from the quantity of main types of BGMS being prescribed combined with the published accuracy, as % results within ±% bands from reference value for the selected strip type. The regression coefficient between the BGMSV and HbA1cV was calculated. To allow for the aggregation of estimated three tests/day over 13 weeks (ie, 300 samples) of actual Blood Glucose (BG) values up to the HbA1c, we multiplied HbA1cV coefficient by √300 to estimate an empirical value for impact of BGMSV on BGV. RESULTS: Four thousand five hundred and twenty-four practice years with 159 700 T1DM patient years where accuracy data were available for more than 80% of strips prescribed were included, with overall BGMSV 6.5% and HbA1c mean of 66.9 mmol/mol (8.3%) with variability of 13 mmol/mol equal to 19% of the mean. At a GP practice level, BGMSV and HbA1cV as % of mean HbA1c (in other words, the spread of HbA1c) were closely related with a regression coefficient of 0.176, P ±4.5 mmol/L from target, compared with the best performing BGMS with BG >±2.2 mmol/L from reference on 1/20 occasions. CONCLUSION: Use of more variable/less accurate BGMS is associated both theoretically and in practice with a larger variability in measured BG and HbA1c, with implications for patient confidence in their day-to-day monitoring experience

Understanding why primary care doctors leave direct patient care: a systematic review of qualitative research

This is the final version. Available on open access from BMJ Publishing Group via the DOI in this recordData availability statement: All data relevant to the study are included in the article or uploaded as supplementary information. No additional data available.Background UK general practitioners (GPs) are leaving direct patient care in significant numbers. We undertook a systematic review of qualitative research to identify factors affecting GPs’ leaving behaviour in the workforce as part of a wider mixed methods study (ReGROUP). Objective To identify factors that affect GPs’ decisions to leave direct patient care. Methods Qualitative interview-based studies were identified and their quality was assessed. A thematic analysis was performed and an explanatory model was constructed providing an overview of factors affecting UK GPs. Non-UK studies were considered separately. Results Six UK interview-based studies and one Australian interview-based study were identified. Three central dynamics that are key to understanding UK GP leaving behaviour were identified: factors associated with low job satisfaction, high job satisfaction and those linked to the doctor–patient relationship. The importance of contextual influence on job satisfaction emerged. GPs with high job satisfaction described feeling supported by good practice relationships, while GPs with poor job satisfaction described feeling overworked and unsupported with negatively impacted doctor–patient relationships. Conclusions Many GPs report that job satisfaction directly relates to the quality of the doctor–patient relationship. Combined with changing relationships with patients and interfaces with secondary care, and the gradual sense of loss of autonomy within the workplace, many GPs report a reduction in job satisfaction. Once job satisfaction has become negatively impacted, the combined pressure of increased patient demand and workload, together with other stress factors, has left many feeling unsupported and vulnerable to burn-out and ill health, and ultimately to the decision to leave general practice

Advancing Tests of Relativistic Gravity via Laser Ranging to Phobos

Phobos Laser Ranging (PLR) is a concept for a space mission designed to advance tests of relativistic gravity in the solar system. PLR's primary objective is to measure the curvature of space around the Sun, represented by the Eddington parameter $\gamma$, with an accuracy of two parts in $10^7$, thereby improving today's best result by two orders of magnitude. Other mission goals include measurements of the time-rate-of-change of the gravitational constant, $G$ and of the gravitational inverse square law at 1.5 AU distances--with up to two orders-of-magnitude improvement for each. The science parameters will be estimated using laser ranging measurements of the distance between an Earth station and an active laser transponder on Phobos capable of reaching mm-level range resolution. A transponder on Phobos sending 0.25 mJ, 10 ps pulses at 1 kHz, and receiving asynchronous 1 kHz pulses from earth via a 12 cm aperture will permit links that even at maximum range will exceed a photon per second. A total measurement precision of 50 ps demands a few hundred photons to average to 1 mm (3.3 ps) range precision. Existing satellite laser ranging (SLR) facilities--with appropriate augmentation--may be able to participate in PLR. Since Phobos' orbital period is about 8 hours, each observatory is guaranteed visibility of the Phobos instrument every Earth day. Given the current technology readiness level, PLR could be started in 2011 for launch in 2016 for 3 years of science operations. We discuss the PLR's science objectives, instrument, and mission design. We also present the details of science simulations performed to support the mission's primary objectives.Comment: 25 pages, 10 figures, 9 table

On Poincare and logarithmic Sobolev inequalities for a class of singular Gibbs measures

This note, mostly expository, is devoted to Poincar{\'e} and log-Sobolev inequalities for a class of Boltzmann-Gibbs measures with singular interaction. Such measures allow to model one-dimensional particles with confinement and singular pair interaction. The functional inequalities come from convexity. We prove and characterize optimality in the case of quadratic confinement via a factorization of the measure. This optimality phenomenon holds for all beta Hermite ensembles including the Gaussian unitary ensemble, a famous exactly solvable model of random matrix theory. We further explore exact solvability by reviewing the relation to Dyson-Ornstein-Uhlenbeck diffusion dynamics admitting the Hermite-Lassalle orthogonal polynomials as a complete set of eigenfunctions. We also discuss the consequence of the log-Sobolev inequality in terms of concentration of measure for Lipschitz functions such as maxima and linear statistics.Comment: Minor improvements. To appear in Geometric Aspects of Functional Analysis -- Israel Seminar (GAFA) 2017-2019", Lecture Notes in Mathematics 225