Are routinely collected NHS administrative records suitable for endpoint identification in clinical trials? Evidence from the West of Scotland coronary prevention study

Background: Routinely collected electronic patient records are already widely used in epidemiological research. In this work we investigated the potential for using them to identify endpoints in clinical trials.<p></p> Methods: The events recorded in the West of Scotland Coronary Prevention Study (WOSCOPS), a large clinical trial of pravastatin in middle-aged hypercholesterolaemic men in the 1990s, were compared with those in the record-linked deaths and hospitalisations records routinely collected in Scotland.<p></p> Results: We matched 99% of fatal study events by date. We showed excellent matching (97%) of the causes of fatal endpoint events and good matching (.80% for first events) of the causes of nonfatal endpoint events with a slightly lower rate of mismatching of record linkage than study events (19% of first study myocardial infarctions (MI) and 4% of first record linkage MIs not matched as MI). We also investigated the matching of non-endpoint events and showed a good level of matching, with .78% of first stroke/TIA events being matched as stroke/TIA. The primary reasons for mismatches were record linkage data recording readmissions for procedures or previous events, differences between the diagnoses in the routinely collected data and the conclusions of the clinical trial expert adjudication committee, events occurring outside Scotland and therefore being missed by record linkage data, miscoding of cardiac events in hospitalisations data as ‘unspecified chest pain’, some general miscoding in the record linkage data and some record linkage errors.<p></p> Conclusions: We conclude that routinely collected data could be used for recording cardiovascular endpoints in clinical trials and would give very similar results to rigorously collected clinical trial data, in countries with unified health systems such as Scotland. The endpoint types would need to be carefully thought through and an expert endpoint adjudication committee should be involved.<p></p&gt

Effect of socioeconomic deprivation on waiting time for cardiac surgery: retrospective cohort study

OBJECTIVE: To determine whether the priority given to patients referred for cardiac surgery is associated with socioeconomic status. DESIGN: Retrospective study with multivariate logistic regression analysis of the association between deprivation and classification of urgency with allowance for age, sex, and type of operation. Multivariate linear regression analysis was used to determine association between deprivation and waiting time within each category of urgency, with allowance for age, sex, and type of operation. SETTING: NHS waiting lists in Scotland. PARTICIPANTS: 26 642 patients waiting for cardiac surgery, 1 January 1986 to 31 December 1997. MAIN OUTCOME MEASURES: Deprivation as measured by Carstairs deprivation category. Time spent on NHS waiting list. RESULTS: Patients who were most deprived tended to be younger and were more likely to be female. Patients in deprivation categories 6 and 7 (most deprived) waited about three weeks longer for surgery than those in category 1 (mean difference 24 days, 95% confidence interval 15 to 32). Deprived patients had an odds ratio of 0.5 (0.46 to 0.61) for having their operations classified as urgent compared with the least deprived, after allowance for age, sex, and type of operation. When urgent and routine cases were considered separately, there was no significant difference in waiting times between the most and least deprived categories. CONCLUSIONS: Socioeconomically deprived patients are thought to be more likely to develop coronary heart disease but are less likely to be investigated and offered surgery once it has developed. Such patients may be further disadvantaged by having to wait longer for surgery because of being given lower priority

The Formation of Ice Giants in a Packed Oligarchy: Instability and Aftermath

As many as 5 ice giants--Neptune-mass planets composed of 90% ice and rock and 10% hydrogen--are thought to form at heliocentric distances of 10-25 AU on closely packed orbits spaced ~5 Hill radii apart. Such oligarchies are ultimately unstable. Once the parent disk of planetesimals is sufficiently depleted, oligarchs perturb one another onto crossing orbits. We explore both the onset and the outcome of the instability through numerical integrations, including dynamical friction cooling of planets by a planetesimal disk whose properties are held fixed. To trigger instability and the ejection of the first ice giant in systems having an original surface density in oligarchs of Sigma ~ 1 g/cm^2, the disk surface density s must fall below 0.1 g/cm^2. Ejections are predominantly by Jupiter and occur within 10 Myr. To eject more than 1 oligarch requires s < 0.03 g/cm^2. Systems starting with up to 4 oligarchs in addition to Jupiter and Saturn can readily yield solar-system-like outcomes in which 2 surviving ice giants lie inside 30 AU and have their orbits circularized by dynamical friction. Our numerical simulations support the idea that planetary systems begin in more crowded and compact configurations, like those of shear-dominated oligarchies. In contrast to previous studies, we identify s < 0.1 Sigma as the regime relevant for understanding the evolution of the outer solar system, and we encourage future studies to concentrate on this regime while relaxing our assumption of a fixed planetesimal disk.Comment: Accepted to ApJ Jan 27. Incorporates comments from the referee and community at large. 15 pages, 14 figures, including 7 colo

Gravitons and Lightcone Fluctuations II: Correlation Functions

A model of a fluctuating lightcone due to a bath of gravitons is further investigated. The flight times of photons between a source and a detector may be either longer or shorter than the light propagation time in the background classical spacetime, and will form a Gaussian distribution centered around the classical flight time. However, a pair of photons emitted in rapid succession will tend to have correlated flight times. We derive and discuss a correlation function which describes this effect. This enables us to understand more fully the operational significance of a fluctuating lightcone. Our results may be combined with observational data on pulsar timing to place some constraints on the quantum state of cosmological gravitons.Comment: 16 pages and two figures, uses eps

Maxwell symmetries and some applications

The Maxwell algebra is the result of enlarging the Poincar\'{e} algebra by six additional tensorial Abelian generators that make the fourmomenta non-commutative. We present a local gauge theory based on the Maxwell algebra with vierbein, spin connection and six additional geometric Abelian gauge fields. We apply this geometric framework to the construction of Maxwell gravity, which is described by the Einstein action plus a generalized cosmological term. We mention a Friedman-Robertson-Walker cosmological approximation to the Maxwell gravity field equations, with two scalar fields obtained from the additional gauge fields. Finally, we outline further developments of the Maxwell symmetries framework.Comment: 8pages. Presented at the XV-th International Conf. on 'Symmetry Methods in Physics' (Dubna, July 2011) and at the '3rd Galileo-Xu Guangqi meeting' (Beijing, October 2011), to appear in IJMP

Long-term impact on healthcare resource utilization of statin treatment, and its cost effectiveness in the primary prevention of cardiovascular disease: a record linkage study

Aims: To assess the impact on healthcare resource utilization, costs, and quality of life over 15 years from 5 years of statin use in men without a history of myocardial infarction in the West of Scotland Coronary Prevention Study (WOSCOPS).&lt;p&gt;&lt;/p&gt; Methods: Six thousand five hundred and ninety-five participants aged 45–54 years were randomized to 5 years treatment with pravastatin (40 mg) or placebo. Linkage to routinely collected health records extended follow-up for secondary healthcare resource utilization to 15 years. The following new results are reported: cause-specific first and recurrent cardiovascular hospital admissions including myocardial infarction, heart failure, stroke, coronary revascularization and angiography; non-cardiovascular hospitalization; days in hospital; quality-adjusted life years (QALYs); costs of pravastatin treatment, treatment safety monitoring, and hospital admissions.&lt;p&gt;&lt;/p&gt; Results: Five years treatment of 1000 patients with pravastatin (40 mg/day) saved the NHS £710 000 (P &#60; 0.001), including the cost of pravastatin and lipid and safety monitoring, and gained 136 QALYs (P = 0.017) over the 15-year period. Benefits per 1000 subjects, attributable to prevention of cardiovascular events, included 163 fewer admissions and a saving of 1836 days in hospital, with fewer admissions for myocardial infarction, stroke, heart failure and coronary revascularization. There was no excess in non-cardiovascular admissions or costs (or in admissions associated with diabetes or its complications) and no evidence of heterogeneity of effect over sub-groups defined by baseline cardiovascular risk.&lt;p&gt;&lt;/p&gt; Conclusion: Five years' primary prevention treatment of middle-aged men with a statin significantly reduces healthcare resource utilization, is cost saving, and increases QALYs. Treatment of even younger, lower risk individuals is likely to be cost-effective.&lt;p&gt;&lt;/p&gt

Blood rheology, cardiovascular risk factors, and cardiovascular disease: The West of Scotland Coronary Prevention Study

The West of Scotland Coronary Prevention Study (WOSCOPS) showed that pravastatin reduced the risk of coronary heart disease (CHD) events in 6,595 middle-aged hypercholesterolaemic men aged 45-64 years without prior myocardial infarction followed for an average of 4.9 years. We hypothesised prospectively (a) that baseline levels of haemorheological variables were related to baseline and incident CHD and to mortality; and (b) that reduction in lipoproteins by pravastatin would lower plasma and blood viscosity, a potential contributory mechanism to CHD events. We therefore studied plasma and blood viscosity, fibrinogen, haematocrit, and blood cell counts at baseline and 1 year. At baseline, plasma and blood viscosity were related to risk factors, CHD measures, and claudication. On univariate analysis, baseline levels of all rheological variables (except platelet count) were related to incident CHD; CHD mortality; and total mortality. On multivariate analysis including baseline CHD and risk factors, plasma and blood viscosity, haematocrit and white cell count each remained significantly associated with incident CHD; while fibrinogen remained an independent predictor of mortality (all p&lt;0.03). After one year, lipoprotein reduction by pravastatin was associated with significant reductions (about one quarter of a standard deviation) in plasma viscosity (mean difference 0.02 mPa.s, p&lt;0.001) and in blood viscosity (mean difference 0.06 mPa.s, p&lt;0.001), but was not associated with significant changes in other rheological variables. We therefore suggest that pravastatin therapy, which reduces elevated lipoproteins in hypercholesterolaemic men, may lower risks of CHD and mortality partly by lowering plasma and blood viscosity. Further studies are required to test this hypothesis

Cosmological and Black Hole Horizon Fluctuations

The quantum fluctuations of horizons in Robertson-Walker universes and in the Schwarzschild spacetime are discussed. The source of the metric fluctuations is taken to be quantum linear perturbations of the gravitational field. Lightcone fluctuations arise when the retarded Green's function for a massless field is averaged over these metric fluctuations. This averaging replaces the delta-function on the classical lightcone with a Gaussian function, the width of which is a measure of the scale of the lightcone fluctuations. Horizon fluctuations are taken to be measured in the frame of a geodesic observer falling through the horizon. In the case of an expanding universe, this is a comoving observer either entering or leaving the horizon of another observer. In the black hole case, we take this observer to be one who falls freely from rest at infinity. We find that cosmological horizon fluctuations are typically characterized by the Planck length. However, black hole horizon fluctuations in this model are much smaller than Planck dimensions for black holes whose mass exceeds the Planck mass. Furthermore, we find black hole horizon fluctuations which are sufficiently small as not to invalidate the semiclassical derivation of the Hawking process.Comment: 22 pages, Latex, 4 figures, uses eps