Estimating the causal effect of liability to disease on healthcare costs using Mendelian Randomization

Accurate measurement of the effects of disease status on healthcare costs is important in the pragmatic evaluation of interventions but is complicated by endogeneity bias. Mendelian Randomization, the use of random perturbations in germline genetic variation as instrumental variables, can avoid these limitations. We used a novel Mendelian Randomization analysis to model the causal impact on inpatient hospital costs of liability to six prevalent diseases and health conditions: asthma, eczema, migraine, coronary heart disease, Type 2 diabetes, and depression. We identified genetic variants from replicated genome-wide associations studies and estimated their association with inpatient hospital costs on over 300,000 individuals. There was concordance of findings across varieties of sensitivity analyses, including stratification by sex and methods robust to violations of the exclusion restriction. Results overall were imprecise and we could not rule out large effects of liability to disease on healthcare costs. In particular, genetic liability to coronary heart disease had substantial impacts on costs.     

Magnified Risks From Cigarette Smoking for Coronary Prone Families in Utah

The contribution of currently accepted risk factors to the familiality of early coronary heart disease (CHD) is poorly understood. In a telephone and mail survey, risk factor and disease morbidity and mortality data were collected from 100 proband and 185 control families encompassing about 40,000 person-years of experience. Probands were white married men who had died of CHD by age 45. There was a threefold increase in CHD incidence among first-degree relatives of probands compared with control families. In all, 67% of probands had at least one first-degree relative with early CHD, and 29% had two or more first-degree relatives with early CHD compared with 8% of the control families with two or more cases of early CHD.The most striking new finding of this study is the apparently magnified liability of cigarette smoking in families prone to have early coronary heart disease. This effect was seen strongly at younger ages (under 50). Furthermore, in about a third of all families with a history of early CHD, smoking seemed to be the only risk factor contributing to the familial occurrence of the disease. The findings show a large excess absolute risk for CHD among smoking members of proband families and further suggest a possibly heritable susceptibility to the deleterious effects of smoking in many families prone to early coronary disease. Modification of coronary risk factors, especially cigarette smoking, would be of greatest benefit among members of high-risk families.     

FACTORS IN CORONARY ARTERY DISEASE—Cigarette Smoking and Exercise

A study was made of certain information from studies of the State Department of Public Health which bear upon the hypotheses that cigarette-smoking and physical exercise are factors in coronary artery disease. The data supported an association of the disease with cigarette smoking, but not with exercise. An incidental finding was a strong relationship between coronary heart disease and the beginning of the wearing of reading glasses or bifocals at an early age.In the present state of investigations aimed at determining the etiology of coronary artery disease it appears desirable to give serious consideration to multiple factors rather than seeking to find a single cause.     

Debate: at what level of coronary heart disease risk should a statin be prescribed?

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are effective treatments for the primary and secondary prevention of coronary heart disease, but an outstanding issue is determining who should have such treatment. The benefit from treatment with statins appears to be proportional to the underlying risk of coronary heart disease and independent of the factors increasing risk. Most benefit will therefore be achieved by treating people at increased risk of coronary heart disease. Statins reduce coronary morbidity even when the risk of coronary heart disease is relatively low (6% over 10 years), but reduction in all-cause mortality, the true measure of safety has been shown only when the risk of a major coronary heart disease event is 15% over 10 years or greater. At this level of risk patients appear willing to take treatment to gain the benefit expected from statin treatment, and the cost effectiveness of statin treatment is within the range accepted for other treatments. The major impediments to the systematic introduction of statin treatment at this level of risk are the very high overall cost and the large workload in countries like Britain, where the population risk of coronary heart disease is high. For this reason, recent British guidelines correctly advise statin treatment for secondary prevention and primary prevention when the 10 year coronary heart disease risk is 30% or greater as the first priority, moving to a lower coronary heart disease threshold for primary prevention only when resources permit.     

Factors in coronary artery disease: cigarette smoking and exercise

A study was made of certain information from studies of the State Department of Public Health which bear upon the hypotheses that cigarette-smoking and physical exercise are factors in coronary artery disease. The data supported an association of the disease with cigarette smoking, but not with exercise. An incidental finding was a strong relationship between coronary heart disease and the beginning of the wearing of reading glasses or bifocals at an early age. In the present state of investigations aimed at determining the etiology of coronary artery disease it appears desirable to give serious consideration to multiple factors rather than seeking to find a single cause.     

Acquired hemophilia in a patient with myeloma.

The generally accepted indications for stress testing in patients with coronary artery disease include confirming the diagnosis of angina, determining the limitation of activity caused by angina, assessing prognosis in patients with known coronary artery disease, assessing perioperative risk, and evaluating responses to therapy. In patients with a clinical scenario strongly suggestive of angina, testing is not necessary to diagnose coronary artery disease. The exercise treadmill-electrocardiogram test is the oldest and most extensively used stress test and can be reliably performed in patients who are clinically stable and who have an interpretable resting electrocardiogram. The addition of myocardial imaging agents such as thallium 201, technetium Tc 99m sestamibi, and technetium Tc 99m teboroxime increases the sensitivity and specificity for detecting coronary disease. Pharmacologic agents such as dipyridamole, adenosine, and dobutamine may be used in patients who cannot exercise adequately. Myocardial ischemia can also be evaluated by echocardiography, computed tomography, or magnetic resonance imaging, especially when additional information such as left ventricular and valvular function is desired. We review the indications for the noninvasive evaluation of coronary artery disease and the rationale for selecting a diagnostic test.     

Cholesterol lowering and the vessel wall: new insights and future perspectives.

The basis for most acute coronary events is either rupture or fissuring of unstable atherosclerotic plaques with subsequent thrombosis leading to coronary artery occlusion. The development of atherosclerotic plaques takes several decades, but the mechanical features determining its stability and the risk of rupture can change very rapidly depending on a number of internal factors. Unstable plaques have a large lipid core, a thin overlying fibrous cap and an abundance of inflammatory cells. The most important factor determining the plaque stability is the plasma level of atherogenic LDL particles. Increased levels of these particles cause endothelial dysfunction with impaired vasodilatation capacity and prevalence of vasoconstriction, maintain inflammatory infiltration of the plaque, impair the strength of the fibrous cap and facilitate aggregation and coagulation. Effective lowering of plasma cholesterol by pharmacological and non-pharmacological means can revert most of these processes and increase the plaque's mechanical stability within several hours to days. Lipid lowering therapy can therefore decrease the risk of acute coronary events within a very short space of time. Thus a radical decrease in lipid levels, along with modification of other risk factors, may become the cornerstone for treatment of acute coronary syndromes, in addition to being an effective treatment in primary and secondary prevention of coronary heart disease (CHD).     

Analyzing the relationship between age at onset and risk to relatives.

Correlations in age at onset between relatives affect risk to relatives of a given age. Either an increase or a decrease in risk may be observed for a relative of a proband, according to whether there is a causal relationship between liability to disease and age at onset. Likelihood formulas are given for pairs of relatives under a number of different sampling schemes, and it is shown how data collected from relatives enable maximum-likelihood estimation of parameters of a linear model relating disease liability and age at onset. A genotype-environment extension of this model was fitted to data on age at onset for schizophrenia that were obtained from the National Academy of Sciences-National Research Council Twin Registry. Age at onset is correlated between twins, but this correlation appears to be associated with factors that are separate from those which affect liability to disease. However, even this relatively large sample of twins is too small to draw firm conclusions about any causal relationship between disease liability and onset.     

Adipokines and coronary vasomotor dysfunction

Research in the last 10-15 years has shown that fat cells (adipocytes) produce and release proteins with specific biologic activities. These proteins, termed adipokines, include the hormones leptin, adiponectin, and resistin. Adipose tissue is now recognized as an active endocrine organ. With the obesity pandemic swelling in the Western world, ongoing research is aimed at determining the biologic links between obesity and cardiovascular disease. This review presents basic historical background information on the major adipokines, introduces findings from clinical studies associating adipokines with cardiovascular disease, and summarizes results from recent basic science research studies of mechanisms of adipokine-induced cardiovascular dysfunction. Particular emphasis is placed on the action of adipokines in the coronary circulation-especially effects of adipokines on endothelial function, as endothelial damage is likely a critical event initiating atherosclerotic coronary artery disease.     

L’apport de la fusion scintigraphie myocardique–scanner coronaire

The purpose is to assess the added information provided by the fusion from the SPECT and the CT coronary angiography, in the identification of the coronary artery – related ischemia (reversible defects) and the coronary artery-related infarction (fixed defects). Compared with the sole analyse of SPECT; addition of fused SPECT/CT images appears to enhance the ability to identify the ischemia – related artery. This might be particularly useful for determining the optimal revascularisation procedure in patients with multivessel disease.     

Techniques d’imagerie de la cardiopathie ischémique : le point de vue du clinicien

Coronary angiography often remains an unavoidable gold standard in cardiology practice for determining the severity, extent and prognosis of coronary artery disease and for therapeutic decision making, although established non-invasive testing – such as myocardial perfusion imaging or stress echocardiography – have demonstrated their diagnostic value and their incremental pronostic value over coronary angiography. Newer noninvasive techniques, such as multidetector computed tomography and magnetic resonance imaging, are currently being validated and will very soon be considered as alternatives to these imaging modalities in clinical practice. Facing this wide choice of tests, the cardiology community has the difficult task to determine the role and place of these various investigating techniques and to evaluate their resource implications, in other words, to optimize the cost-efficacy and ratios in the management of coronary artery disease.     

Regressive logistic models for familial diseases: a formulation assuming an underlying liability model

Statistical models have been developed to delineate the major-gene and non-major-gene factors accounting for the familial aggregation of complex diseases. The mixed model assumes an underlying liability to the disease, to which a major gene, a multifactorial component, and random environment contribute independently. Affection is defined by a threshold on the liability scale. The regressive logistic models assume that the logarithm of the odds of being affected is a linear function of major genotype, phenotypes of antecedents and other covariates. An equivalence between these two approaches cannot be derived analytically. I propose a formulation of the regressive logistic models on the supposition of an underlying liability model of disease. Relatives are assumed to have correlated liabilities to the disease; affected persons have liabilities exceeding an estimable threshold. Under the assumption that the correlation structure of the relatives' liabilities follows a regressive model, the regression coefficients on antecedents are expressed in terms of the relevant familial correlations. A parsimonious parameterization is a consequence of the assumed liability model, and a one-to-one correspondence with the parameters of the mixed model can be established. The logits, derived under the class A regressive model and under the class D regressive model, can be extended to include a large variety of patterns of family dependence, as well as gene-environment interactions.     

Intermittent claudication: factors determining outcome.

Two groups of patients were followed up for four to eight years after first referral or admission to hospital for intermittent claudication (IC) in a study of the natural history of the disease and of factors determining its outcome. In one series of 60 patients, those who stopped or reduced smoking after referral had a much improved prognosis. Thus even after the diagnosis of IC it is extremely important that patients should be encouraged to stop smoking, since this correctable factor appears to be of greater importance in determining outcome than other medical risk factors for the disease that are less amenable to treatment. In the second study, 160 patients were followed up for eight years after first hospital admission. They had a total of 480 hospital admissions and had spent 11 190 days in hospital; their life expectancy after the age of 60 was about half that of the general population. Age, coronary artery disease, cerebrovascular disease, and diabetes were associated with an adverse outcome.     

Comparison of estimates and calculations of risk of coronary heart disease by doctors and nurses using different calculation tools in general practice: cross sectional study

ObjectiveTo assess the effect of using different risk calculation tools on how general practitioners and practice nurses evaluate the risk of coronary heart disease with clinical data routinely available in patients'' records.DesignSubjective estimates of the risk of coronary heart disease and results of four different methods of calculation of risk were compared with each other and a reference standard that had been calculated with the Framingham equation; calculations were based on a sample of patients'' records, randomly selected from groups at risk of coronary heart disease.SettingGeneral practices in central England.Participants18 general practitioners and 18 practice nurses.ResultsOnly a minority of patients'' records contained all of the risk factors required for the formal calculation of the risk of coronary heart disease (concentrations of high density lipoprotein (HDL) cholesterol were present in only 21%). Agreement of risk calculations with the reference standard was moderate (κ=0.33-0.65 for practice nurses and 0.33 to 0.65 for general practitioners, depending on calculation tool), showing a trend for underestimation of risk. Moderate agreement was seen between the risks calculated by general practitioners and practice nurses for the same patients (κ=0.47 to 0.58). The British charts gave the most sensitive results for risk of coronary heart disease (practice nurses 79%, general practitioners 80%), and it also gave the most specific results for practice nurses (100%), whereas the Sheffield table was the most specific method for general practitioners (89%).ConclusionsRoutine calculation of the risk of coronary heart disease in primary care is hampered by poor availability of data on risk factors. General practitioners and practice nurses are able to evaluate the risk of coronary heart disease with only moderate accuracy. Data about risk factors need to be collected systematically, to allow the use of the most appropriate calculation tools.

What is already known on this topic

Recent guidelines have recommended determining the risk of coronary heart disease for targeting patients at high risk for primary preventionEstimates of risk have been shown to be inaccurateGeneral practitioners and practice nurses can use risk calculation tools accurately when given patient data in the form of scenarios

What this study adds

Many patients do not have adequate information in their records to allow the risk of coronary heart disease to be calculatedWhen data about risk factors were available, risk calculations made by general practitioners and practice nurses were moderately accurate compared to a reference calculationWhen adequate information about risk factors is not available, subjective estimates are a reasonable alternative to calculating risk     

Evaluation of Industrial-Accidents Management Performance in China

We conducted a quantitative evaluation of the management of industrial accidents for 31 provinces in mainland China through the data envelopment analysis (DEA) method. It was found that there is a significant difference among the provincial accidents-management performances. The characteristics of the provinces with high performances in managing industrial accidents are: developed economy, convenient transportation, advanced technologies, and immediate access to medical care. Factor analysis revealed that the implementation of compulsory auto liability insurance and high population density are correlated with the high management performance of industrial accidents, while population movement and advanced technologies increase the vulnerability to industrial accidents. Further, the work-related injury insurance did not significantly promote management of accidents. Some implications are recommended for both government and business enterprises according to the results.     

How meaningful are heritability estimates of liability?

It is commonly acknowledged that estimates of heritability from classical twin studies have many potential shortcomings. Despite this, in the post-GWAS era, these heritability estimates have come to be a continual source of interest and controversy. While the heritability estimates of a quantitative trait are subject to a number of biases, in this article we will argue that the standard statistical approach to estimating the heritability of a binary trait relies on some additional untestable assumptions which, if violated, can lead to badly biased estimates. The ACE liability threshold model assumes at its heart that each individual has an underlying liability or propensity to acquire the binary trait (e.g., disease), and that this unobservable liability is multivariate normally distributed. We investigated a number of different scenarios violating this assumption such as the existence of a single causal diallelic gene and the existence of a dichotomous exposure. For each scenario, we found that substantial asymptotic biases can occur, which no increase in sample size can remove. Asymptotic biases as much as four times larger than the true value were observed, and numerous cases also showed large negative biases. Additionally, regions of low bias occurred for specific parameter combinations. Using simulations, we also investigated the situation where all of the assumptions of the ACE liability model are met. We found that commonly used sample sizes can lead to biased heritability estimates. Thus, even if we are willing to accept the meaningfulness of the liability construct, heritability estimates under the ACE liability threshold model may not accurately reflect the heritability of this construct. The points made in this paper should be kept in mind when considering the meaningfulness of a reported heritability estimate for any specific disease.     

BORDERLINE INDUSTRIAL INJURIES

Sometimes in cases of injury in which a claim for compensation is made on the basis that the injury is attributable to the claimant''s work, the etiology is not clear cut. Such injuries tend to merge with and to overlap non-industrial ailments.This presentation deals with some of the more troublesome conditions of this order—among them chondromalacia of the patella, causalgia, Sudek''s atrophy, shoulder-hand syndrome, whiplash injury, tenosynovitis, epicondylitis, acoustic trauma and acute coronary occlusion. Often in these conditions, it is almost impossible to determine accurately how much or how little of the associated disability is attributable to industrial cause. In most of them, however, early diagnosis and sympathetic management of injury when it does occur, are of great help in determining compensability and in returning the employe to suitable work.     

Mapping Quantitative Trait Loci for Complex Binary Diseases Using Line Crosses

A composite interval gene mapping procedure for complex binary disease traits is proposed in this paper. The binary trait of interest is assumed to be controlled by an underlying liability that is normally distributed. The liability is treated as a typical quantitative character and thus described by the usual quantitative genetics model. Translation from the liability into a binary (disease) phenotype is through the physiological threshold model. Logistic regression analysis is employed to estimate the effects and locations of putative quantitative trait loci (our terminology for a single quantitative trait locus is QTL while multiple loci are referred to as QTLs). Simulation studies show that properties of this mapping procedure mimic those of the composite interval mapping for normally distributed data. Potential utilization of the QTL mapping procedure for resolving alternative genetic models (e.g., single- or two-trait-locus model) is discussed.     

Associations of low density lipoprotein particle composition with atherogenicity

PURPOSE OF REVIEW: A growing body of data suggests that in addition to LDL-cholesterol concentrations, compositional properties of LDL, including size and fatty acid composition, are important in determining the relative degree of atherogenicity. This review examines current research in this field to evaluate which properties of LDL may most directly influence the risk of coronary heart disease. RECENT FINDINGS: The presence of small dense LDL has been correlated with an increased risk of coronary heart disease, but this has not been shown to be fully independent of related factors such as elevated plasma triacylglycerol concentrations. An increased susceptibility of small dense LDL to in-vitro oxidation has also been demonstrated, but its importance to coronary heart disease risk has not been established. Other studies have found that the presence of enlarged LDL, modified (oleate enriched) fatty acyl composition of LDL, and higher numbers of LDL particles in plasma also are endpoints associated with an increased risk of coronary heart disease. SUMMARY: LDL size may indicate a metabolic condition associated with increased CHD risk as opposed to the direct promotion of atherosclerosis by specific particle types of LDL. In most claims of detrimental effects of small dense LDL, neither LDL particle concentrations nor the fatty acid composition of the particles were established, both factors being important in contributing to the atherogenic potential of LDL. The predisposition to premature coronary heart disease cannot currently be objectively assigned to any one type of LDL particle.     

Fluorometric quantitation of adenosine concentration in small samples of extracellular fluid.

Adenosine is a naturally occurring nucleoside which regulates many physiological processes by interacting with adenosine-specific receptors. Knowledge of the extracellular adenosine concentration at the site of adenosine receptors on target cells is required for an understanding of mechanisms involving the action of the nucleoside. Samples of extracellular fluid which reside in close proximity to the surface of target cells are frequently small in volume. This report describes improvements in accuracy and reliability of a fluorometric assay designed for determining the concentration of adenosine in microliter samples of extracellular fluids. The utility of the assay is demonstrated by determining adenosine concentrations in interstitial and coronary effluent samples from normoxic perfused rat hearts. The assay also clearly detects changes in the interstitial and coronary effluent adenosine levels produced by isoproterenol stimulation or hypoxia. Thus, this assay is useful for determining the adenosine concentration in microliter samples of extracellular fluid and should facilitate investigations dealing with the functions of adenosine.