An epigenome-wide association study meta-analysis of educational attainment.

The epigenome is associated with biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here we provide evidence on the associations between epigenetic modifications-in our case, CpG methylation-and educational attainment (EA), a biologically distal environmental factor that is arguably among the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10 767 individuals. We find nine CpG probes significantly associated with EA. However, robustness analyses show that all nine probes have previously been found to be associated with smoking. Only two associations remain when we perform a sensitivity analysis in the subset of never-smokers, and these two probes are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, the effect sizes of the associations with EA are far smaller than the known associations with the biologically proximal environmental factors alcohol consumption, body mass index, smoking and maternal smoking during pregnancy. Follow-up analyses that combine the effects of many probes also point to small methylation associations with EA that are highly correlated with the combined effects of smoking. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.

Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice.

It is often challenging for the clinician interested in cystic fibrosis (CF) to interpret molecular genetic results, and to integrate them in the diagnostic process. The limitations of genotyping technology, the choice of mutations to be tested, and the clinical context in which the test is administered can all influence how genetic information is interpreted. This paper describes the conclusions of a consensus conference to address the use and interpretation of CF mutation analysis in clinical settings. Although the diagnosis of CF is usually straightforward, care needs to be exercised in the use and interpretation of genetic tests: genotype information is not the final arbiter of a clinical diagnosis of CF or CF transmembrane conductance regulator (CFTR) protein related disorders. The diagnosis of these conditions is primarily based on the clinical presentation, and is supported by evaluation of CFTR function (sweat testing, nasal potential difference) and genetic analysis. None of these features are sufficient on their own to make a diagnosis of CF or CFTR-related disorders. Broad genotype/phenotype associations are useful in epidemiological studies, but CFTR genotype does not accurately predict individual outcome. The use of CFTR genotype for prediction of prognosis in people with CF at the time of their diagnosis is not recommended. The importance of communication between clinicians and medical genetic laboratories is emphasized. The results of testing and their implications should be reported in a manner understandable to the clinicians caring for CF patients.

Genetics of autoimmune diseases: a multistep process.

It has so far been difficult to identify genes behind polygenic autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), and type I diabetes (T1D). With proper animal models, some of the complexity behind these diseases can be reduced. The use of linkage analysis and positional cloning of genes in animal models for RA resulted in the identification of one of the genes regulating severity of arthritis in rats and mice, the Ncf1 gene. The Ncf1 gene encodes for the Ncf1 protein that is involved in production of free oxygen radicals through the NADPH oxidase complex, which opens up a new pathway for therapeutic treatment of inflammatory diseases. In most cases, however, a quantitative trait locus (QTL) is the sum effect of several genes within and outside the QTL, which make positional cloning difficult. Here we will discuss the possibilities and difficulties of gene identification in animal models of autoimmune disorders.

Registered Replication Report: Rand, Greene, and Nowak (2012).

In an anonymous 4-person economic game, participants contributed more money to a common project (i.e., cooperated) when required to decide quickly than when forced to delay their decision (Rand, Greene & Nowak, 2012), a pattern consistent with the social heuristics hypothesis proposed by Rand and colleagues. The results of studies using time pressure have been mixed, with some replication attempts observing similar patterns (e.g., Rand et al., 2014) and others observing null effects (e.g., Tinghög et al., 2013; Verkoeijen & Bouwmeester, 2014). This Registered Replication Report (RRR) assessed the size and variability of the effect of time pressure on cooperative decisions by combining 21 separate, preregistered replications of the critical conditions from Study 7 of the original article (Rand et al., 2012). The primary planned analysis used data from all participants who were randomly assigned to conditions and who met the protocol inclusion criteria (an intent-to-treat approach that included the 65.9% of participants in the time-pressure condition and 7.5% in the forced-delay condition who did not adhere to the time constraints), and we observed a difference in contributions of -0.37 percentage points compared with an 8.6 percentage point difference calculated from the original data. Analyzing the data as the original article did, including data only for participants who complied with the time constraints, the RRR observed a 10.37 percentage point difference in contributions compared with a 15.31 percentage point difference in the original study. In combination, the results of the intent-to-treat analysis and the compliant-only analysis are consistent with the presence of selection biases and the absence of a causal effect of time pressure on cooperation.

Composition of nasal airway surface liquid in cystic fibrosis and other airway diseases determined by X-ray microanalysis.

The ionic composition of the airway surface liquid (ASL) in healthy individuals and in patients with cystic fibrosis (CF) has been debated. Ion transport properties of the upper airway epithelium are similar to those of the lower airways and it is easier to collect nasal ASL from the nose. ASL was collected with ion exchange beads, and the elemental composition of nasal fluid was determined by X-ray microanalysis in healthy subjects, CF patients, CF heterozygotes, patients with rhinitis, and with primary ciliary dyskinesia (PCD). In healthy subjects, the ionic concentrations were approximately isotonic. In CF patients, CF heterozygotes, rhinitis, and PCD patients, [Na] and [Cl] were significantly higher compared when compared with those in controls. [K] was significantly higher in CF and PCD patients compared with that in controls. Severely affected CF patients had higher ionic concentrations in their nasal ASL than in patients with mild or moderate symptoms. Female CF patients had higher levels of Na, Cl, and K than male patients. As higher salt concentrations in the ASL are also found in other patients with airway diseases involving chronic inflammation, it appears likely that inflammation-induced epithelial damage is important in determining the ionic composition of the ASL.

Is misoprostol cost-effective in the prevention of nonsteroidal anti-inflammatory drug-induced gastropathy in patients with chronic arthritis? A review of conflicting economic evaluations.

Whether misoprostol, a synthetic prostaglandin E1 analogue, should be routinely prescribed along with nonsteroidal anti-inflammatory drugs (NSAIDS) to prevent gastric damage is of great clinical importance and has profound cost implications. No consensus exists on whether misoprostol cotherapy results in a cost-saving, is cost-effective, or is costly. The different conclusions reached by five economic evaluations of misoprostol can be explained solely by the assumed absolute risk reduction of symptomatic ulcer, which was more than seven times greater in the studies that concluded that misoprostol was cost-effective than in a study that concluded misoprostol to be costly. Since no study has directly shown the effectiveness of misoprostol cotherapy in preventing clinically significant ulcer disease (ie, hemorrhage and perforation), it is impossible to judge which assumptions are most appropriate. The absence of firm data on the rate of NSAID-induced gastric ulcers reduced by misoprostol makes it impossible to conclude whether it is cost-effective in patients with chronic arthritis who use NSAIDS.

Resource utilization and costs of stroke unit care integrated in a care continuum: A 1-year controlled, prospective, randomized study in elderly patients: the Göteborg 70+ Stroke Study.

BACKGROUND AND PURPOSE: The aim of the present study was to examine resource utilization during a 12-month period after acute stroke in elderly patients randomized to care in an acute stroke unit integrated with a care continuum compared with conventional care in general medical wards. A secondary aim was to describe costs related to the severity of stroke. METHODS: Two hundred forty-nine consecutive patients aged >/=70 years with acute stroke within 7 days before admission, living in their own homes in Göteborg, Sweden, without recognized need of care were randomized to 2 groups: 166 patients were assigned to nonintensive stroke unit care with a care continuum, and 83 patients were assigned to conventional care. There was no difference in mortality or the proportion of patients living at home after 1 year. Main outcomes were costs from inpatient care, outpatient care, and informal care. RESULTS: Mean annual cost per patient was 170, 000 Swedish crowns (SEK) (equivalent to $25,373) and 191,000 SEK ($28,507) in the stroke unit and the general medical ward groups, respectively (P:=NS). Seventy percent of the total cost was for inpatient care, and 30% was for outpatient and informal care. For patients with mild, moderate, and severe stroke, the mean annual costs per patient were 107,000 SEK ($15,970), 263,000 SEK ($39, 254), and 220,000 SEK ($32,836), respectively (P:<0.001). There was no statistical difference in age or nonstroke diagnosis. CONCLUSIONS: The total costs the first year did not differ significantly between the treatment groups in this prospective study. The total annual cost per patient showed a very large variation, which was related to stroke severity at onset and not to age or nonstroke diagnoses. Costs other than those for hospital care constituted a substantial fraction of total costs and must be taken into account when organizing the management of stroke patients. The high variability in costs necessitates a larger study to assess long-term cost effectiveness.

A health-economic comparison of diet and drug treatment in obese men with mild hypertension.

OBJECTIVE: To compare dietary and antihypertensive drug treatment in obese men with mild hypertension in economic terms. DESIGN: A 6-week run-in period followed by randomization to either diet or drug treatment, lasting for 1 year. Blood pressure was measured blindly and serum lipid concentrations assessed at run-in and after 1 year. A computer-based model was used in five cost-effectiveness simulations with different assumptions as to the effect upon coronary heart disease risk from the changes in diastolic blood pressure and cholesterol, both total and high-density lipoprotein. A cost-benefit analysis was also performed, calculated as willingness to pay for treatment, as assessed by questionnaire, minus total cost. SETTING: Outpatient clinic in city hospital. PATIENTS: Sixty-four men aged 40-69 years with body mass index > or = 26 kg/m2 and a diastolic blood pressure 90-104 mmHg when untreated were recruited (screening after advertisement in newspaper). Exclusion criteria were diabetes mellitus, organ damage secondary to hypertension, and diseases that might have interfered with compliance and the interpretation of results. Sixty-one patients completed the study. INTERVENTIONS: Dietary treatment was based upon weight reduction and sodium restriction. Drug treatment used a stepped-care approach, with atenolol as the drug of first choice. MAIN OUTCOME MEASURES: Life years gained and willingness to pay. RESULTS: Drug treatment was the preferred option in three of the five cost-effectiveness simulations. The cost-benefit analysis did not show any difference between the two groups. CONCLUSIONS: Non-pharmacological treatment seemed to be less cost-effective than drug treatment. However, more studies and further methodological development are needed to verify this finding.

Interpretation of change scores in ordinal clinical scales and health status measures: the whole may not equal the sum of the parts.

The objective of this study was to analyze the problem of interpreting change scores of ordinal health status measures for clinical research or practice. Methods used included exploration of the generation of change scores in the physical ability scale of the SF-36, one of the most widely used generic health status instruments. Resulting data are presented as the ranking of items according to baseline score; a percentage of patients with severe difficulty and Rasch analysis provided the same rank order of item difficulty. On the interval scale provided by the Rasch model a concentration of items reflecting moderate difficulty occurred. This "inflates" numerical gains for patients with moderate disability compared to patients with very severe or minor physical disability. Calibration of change scores using patient perception of the level of change in function showed important variation of numerical gains with baseline. We conclude that numerically equal gains may differ in their meaning depending on baseline health status. It is recommended that distribution of baseline health status measures and distribution of responders by baseline status be reported in evaluative studies.

Cystic fibrosis mRNA expression in rat brain: cerebral cortex and medial preoptic area.

Cystic fibrosis transmembrane conductance regulator (CFTR) mRNA expression has been found in the medial preoptic area using in situ hybridization, addressing the possibility of CFTR regulation of sexual maturation and reproductive behaviour. CFTR mRNA has also been found in the cortical deep pyramidal layer V implying possible involvement of CFTR in 'motor' function and output control over bodily movements and secretion. CFTR production in the brain regions observed in this study implicate involvement of CFTR in cerebral control over motor/visceral and endocrine systems.

Use of contingent valuation to place a monetary value on pharmacy services: an overview and review of the literature.

An important goal for the pharmacy profession is to quantify the economic value of pharmacy services. The contingent valuation (CV), or willingness-to-pay method, offers one approach to valuing the benefits of pharmacy services. The potential advantage CV offers is that it reflects, in a single monetary amount, the entire range of attributes (both benefits and "nonbenefits") offered by the good or service being valued. This paper provides a brief overview of the CV method and reviews 10 published studies that used a willingness-to-pay question to place a monetary value on pharmacy services. Suggestions for other researchers wishing to use this method are provided.

The cost-effectiveness of hypertension treatment in Sweden: an analysis of the criteria for intervention and the choice of drug treatment.

Results of an analysis of the cost-effectiveness of hypertension treatment in Sweden are presented. The cost per life-year gained decreases with age for both men and women and is relatively low for middle-aged and older men and women even in the blood pressure range 90-94 mmHg. The results indicate that it is in general cost-effective to treat middle-aged and older men and women in Sweden with a diastolic blood pressure > or = 90 mmHg, but that it is questionable whether it is in general cost-effective to treat younger men and women with mild hypertension. It is furthermore shown that ACE-inhibitors and calcium-antagonists may be cost-effective in some patient groups at a high risk of coronary heart disease, if they achieve the epidemiologically expected risk reduction for coronary heart disease. Since an improved risk reduction has not been demonstrated in clinical trials ACE-inhibitors and calcium-antagonists cannot, however, at present be recommended for hypertension treatment in any patient groups unless treatment with diuretics and beta-blockers is contraindicated.

How to assess the economics of hypertension control programmes.

In this paper we summarise the discussion in the session about how to assess the economics of hypertension control programmes. The paper is structured around the four main themes discussed in the session: the methods of economic evaluation, the estimation of costs in an economic evaluation, the estimation of effects in an economic evaluation, and the relationship between economic evaluation and policy-making.

On aggregating QALYs: a comment on Dolan.

Dolan [Dolan, P., 1998, The measurement of individual utility and social welfare. Journal of Health Economics, Vol. 17, pp. 39-52] in a recent paper suggested an empirical method for estimating the shape of the social welfare function. Using a simple theoretical model it is shown that Dolan's proposed empirical method has no theoretical foundation. The main problem with the approach is that it measures only the altruistic values that individuals attach to other peoples' health status and ignores the utility that individuals attach to their own health status.

A note on the estimation of the equity-efficiency trade-off for QALYs.

In this note the veil of ignorance approach is tested as a basis for empirically determining the shape of the social welfare function for QALYs. An experiment is carried out where the participants choose between different societies that differ with respect to per capita QALYs and the distribution of QALYs. The answers are analyzed using logistic regression analysis. According to the results the respondents are willing to give up I QALY in the group with more QALYs to gain 0.45 QALYs in the group with fewer QALYs, but this trade-off is independent of the size of the difference in QALYs between the groups.

The friction cost method: a comment.

The friction cost method has been proposed as an alternative to the human-capital approach of estimating indirect costs. We argue that the friction cost method is based on implausible assumptions not supported by neoclassical economic theory. Furthermore consistently applying the friction cost method would mean that the method should also be applied in the estimation of direct costs, which would mean that the costs of health care programmes are substantially decreased. It is concluded that the friction cost method does not seem to be a useful alternative to the human-capital approach in the estimation of indirect costs.

Standard gamble, time trade-off and rating scale: experimental results on the ranking properties of QALYs.

This paper compares the relative performance of quality adjusted life years (QALYs) based on quality weights elicited by rating scale (RS), time trade-off (TTO) and standard gamble (SG). The standard against which relative performance is assessed is individual preference elicited by direct ranking. The correlation between predicted and direct ranking is significantly higher for TTO-QALYs than for RS-QALYs and SG-QALYs. This holds both based on mean Spearman rank correlation coefficients calculated per individual and based on two social choice rules: the method of majority voting and the Borda rule. Undiscounted TTO-QALYs are more consistent with direct ranking than discounted TTO-QALYs.

Income-related inequality in life-years and quality-adjusted life-years.

We estimate the income-related inequality in Sweden with respect to life-years and quality-adjusted life-years (QALYs). We use a large data set from Sweden with over 40,000 individuals followed up for 10-16 years, to estimate the survival and quality-adjusted survival in different income groups. For both life-years and QALYs, we discover inequalities in health favouring the higher income groups. For men (women) in the youngest age-group (20-29 years), the number of QALYs is 43.7 (45.7) in the lowest income decile and 47.2 (49.0) in the highest income decile.

Willingness to pay for antihypertensive therapy--results of a Swedish pilot study.

In this methodological study the results of a Swedish pilot study about willingness to pay for antihypertensive therapy are presented. The aim of the study was to test the feasibility of the contingent valuation (CV) method in this area. Open-ended and discrete CV questions were compared in a mail questionnaire. The open-ended CV question did not work well. The answers to the discrete question, analysed by logistic regression analysis, indicated a willingness to pay in the range SEK 2500-5000 per year for antihypertensive therapy. Further studies should be undertaken to explore the reliability and the validity of the CV method.

Time spent on waiting lists for medical care: an insurance approach.

In this paper, we develop a simple model of the benefits and costs of being on a waiting list. The model shows that complex factors are in operation, implying that a shorter waiting time need not necessarily be preferred to a longer waiting time. We also present an empirical study, where a sample of Swedes are offered the possibility of purchasing private insurance, thus reducing waiting time for surgery beyond the three-month guarantee offered by the public sector health care system. Respondents could choose between two insurance contracts. A 'spike' model, where the probability of a zero WTP is strictly positive, was developed and estimated to obtain demand functions for private insurance.