Andreas Stang

Coronary Risk Stratification, Discrimination, and Reclassification Improvement Based on Quantification of Subclinical Coronary Atherosclerosis: The Heinz Nixdorf Recall Study

OBJECTIVES The purpose of this study was to determine net reclassification improvement (NRI) and improved risk prediction based on coronary artery calcification (CAC) scoring in comparison with traditional risk factors. BACKGROUND CAC as a sign of subclinical coronary atherosclerosis can noninvasively be detected by CT and has been suggested to predict coronary events. METHODS In 4,129 subjects from the HNR (Heinz Nixdorf Recall) study (age 45 to 75 years, 53% female) without overt coronary artery disease at baseline, traditional risk factors and CAC scores were measured. Their risk was categorized into low, intermediate, and high according to the Framingham Risk Score (FRS) and National Cholesterol Education Panel Adult Treatment Panel (ATP) III guidelines, and the reclassification rate based on CAC results was calculated. RESULTS After 5 years of follow-up, 93 coronary deaths and nonfatal myocardial infarctions occurred (cumulative risk 2.3%; 95% confidence interval: 1.8% to 2.8%). Reclassifying intermediate (defined as 10% to 20% and 6% to 20%) risk subjects with CAC <100 to the low-risk category and with CAC ≥400 to the high-risk category yielded an NRI of 21.7% (p = 0.0002) and 30.6% (p < 0.0001) for the FRS, respectively. Integrated discrimination improvement using FRS variables and CAC was 1.52% (p < 0.0001). Adding CAC scores to the FRS and National Cholesterol Education Panel ATP III categories improved the area under the curve from 0.681 to 0.749 (p < 0.003) and from 0.653 to 0.755 (p = 0.0001), respectively. CONCLUSIONS CAC scoring results in a high reclassification rate in the intermediate-risk cohort, demonstrating the benefit of imaging of subclinical coronary atherosclerosis. Our study supports its application, especially in carefully selected individuals with intermediate risk.

Residential Exposure to Traffic Is Associated With Coronary Atherosclerosis

Background— Long-term exposure to fine-particulate-matter (PM2.5) air pollution may accelerate the development and progression of atherosclerosis. We investigated the associations of long-term residential exposure to traffic and fine particulate matter with the degree of coronary atherosclerosis. Methods and Results— We used baseline data on 4494 participants (age 45 to 74 years) from the German Heinz Nixdorf Recall Study, a population-based, prospective cohort study that started in 2000. To assess exposure differences, distances between residences and major roads were calculated, and annual fine particulate matter concentrations, derived from a small-scale dispersion model, were assigned to each address. The main outcome was coronary artery calcification (CAC) assessed by electron-beam computed tomography. We evaluated the association between air pollution and CAC with logistic and linear regression analyses, controlling for individual level risk factors of coronary atherosclerosis. Compared with participants living >200 m away from a major road, participants living within 50, 51 to 100, and 101 to 200 m had odds ratios of 1.63 (95% CI, 1.14 to 2.33), 1.34 (95% CI, 1.00 to 1.79), and 1.08 (95% CI, 0.85 to 1.39), respectively, for a high CAC (CAC above the age- and gender-specific 75th percentile). A reduction in the distance between the residence and a major road by half was associated with a 7.0% (95% CI, 0.1 to 14.4) higher CAC. Fine particulate matter exposure was associated with CAC only in subjects who had not been working full-time for at least 5 years. Conclusions— Long-term residential exposure to high traffic is associated with the degree of coronary atherosclerosis.

Chronic Residential Exposure to Particulate Matter Air Pollution and Systemic Inflammatory Markers

Background Long-term exposure to urban air pollution may accelerate atherogenesis, but mechanisms are still unclear. The induction of a low-grade systemic inflammatory state is a plausible mechanistic pathway. Objectives: We analyzed the association of residential long-term exposure to particulate matter (PM) and high traffic with systemic inflammatory markers. Methods We used baseline data from the German Heinz Nixdorf Recall Study, a population-based, prospective cohort study of 4,814 participants that started in 2000. Fine PM [aerodynamic diameter ≤ 2.5 μm (PM2.5)] exposure based on a small-scale dispersion and chemistry transport model was assigned to each home address. We calculated distances between residences and major roads. Long-term exposure to air pollution (annual PM2.5 and distance to high traffic) and concentration of inflammatory markers [high-sensitivity C-reactive protein (hs-CRP) and fibrinogen] on the day of the baseline visit were analyzed with sex-stratified multiple linear regression, controlling for individual-level risk factors. Results In the adjusted analysis, a cross-sectional exposure difference of 3.91 μg/m3 in PM2.5 (interdecile range) was associated with increases in hs-CRP of 23.9% [95% confidence interval (CI), 4.1 to 47.4%] and fibrinogen of 3.9% (95% CI, 0.3 to 7.7%) in men, whereas we found no association in women. Chronic traffic exposure was not associated with inflammatory markers. Short-term exposures to air pollutants and temperature did not influence the results markedly. Conclusions Our study indicates that long-term residential exposure to high levels of PM2.5 is associated with systemic inflammatory markers in men. This might provide a link between air pollution and coronary atherosclerosis.

Baseline recruitment and analyses of nonresponse of the Heinz Nixdorf Recall Study: identifiability of phone numbers as the major determinant of response.

The Heinz Nixdorf Recall Study is an ongoing population-based prospective cardiovascular cohort study of the Ruhr area in Germany. This paper focuses on the recruitment strategy and its response results including a comparison of participants of the baseline examination with nonparticipants. Random samples of the general population were drawn from residents’ registration offices including men and women aged 45–74 years. We used a multi-mode contact approach including an invitational letter, a maximum of two reminder letters and phone calls for the recruitment of study subjects. Nonparticipants were asked to fill in a short questionnaire. We calculated proportions of response, contact, cooperation and recruitment efficacy to characterize the participation. Overall, 4487 eligible subjects participated in our study. Although the elderly (65–75 years) had the highest contact proportion, the cooperation proportion was the lowest among both men and women. The recruitment efficacy proportion was highest among subjects aged 55–64 years. The identifiability of the phone number of study subjects was an important determinant of response. The recruitment efficacy proportion among subjects without an identified phone number was 11.4% as compared to 65.3% among subjects with an identified phone number. The majority of subjects agreed to participate after one invitational letter only (52.6%). A second reminding letter contributed only very few participants to the study. Nonparticipants were more often current smokers than participants and less often belonged to the highest social class. Living in a regular relationship with a partner was more often reported among participants than nonparticipants.

The possible role of radiofrequency radiation in the development of uveal melanoma.

There are few epidemiologic studies dealing with electromagnetic radiation and uveal melanoma. The majority of these studies are exploratory and are based on job and industry titles only. We conducted a hospital-based and population-based case-control study of uveal melanoma and occupational exposures to different sources of electromagnetic radiation, including radiofrequency radiation. We then pooled these results. We interviewed a total of 118 female and male cases with uveal melanoma and 475 controls matching on sex, age, and study regions. Exposure to radiofrequency-transmitting devices was rated as (a) no radiofrequency radiation exposure, (b) possible exposure to mobile phones, or (c) probable/certain exposure to mobile phones. Exposures were rated independently by two of the authors who did not know case or control status. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). We found an elevated risk for exposure to radiofrequency-transmitting devices (exposure to radio sets, OR = 3.0, 95% CI = 1.4–6.3; probable/certain exposure to mobile phones, OR = 4.2, 95% CI = 1.2–14.5). Other sources of electromagnetic radiation such as high-voltage lines, electrical machines, complex electrical environments, visual display terminals, or radar units were not associated with uveal melanoma. This is the first study describing an association between radiofrequency radiation exposure and uveal melanoma. Several methodologic limitations prevent our results from providing clear evidence on the hypothesized association.

The ongoing tyranny of statistical significance testing in biomedical research

Since its introduction into the biomedical literature, statistical significance testing (abbreviated as SST) caused much debate. The aim of this perspective article is to review frequent fallacies and misuses of SST in the biomedical field and to review a potential way out of the fallacies and misuses associated with SSTs. Two frequentist schools of statistical inference merged to form SST as it is practised nowadays: the Fisher and the Neyman-Pearson school. The P-value is both reported quantitatively and checked against the α-level to produce a qualitative dichotomous measure (significant/nonsignificant). However, a P-value mixes the estimated effect size with its estimated precision. Obviously, it is not possible to measure these two things with one single number. For the valid interpretation of SSTs, a variety of presumptions and requirements have to be met. We point here to four of them: study size, correct statistical model, correct causal model, and absence of bias and confounding. It has been stated that the P-value is perhaps the most misunderstood statistical concept in clinical research. As in the social sciences, the tyranny of SST is still highly prevalent in the biomedical literature even after decades of warnings against SST. The ubiquitous misuse and tyranny of SST threatens scientific discoveries and may even impede scientific progress. In the worst case, misuse of significance testing may even harm patients who eventually are incorrectly treated because of improper handling of P-values. For a proper interpretation of study results, both estimated effect size and estimated precision are necessary ingredients.

Quantification of coronary atherosclerosis and inflammation to predict coronary events and all-cause mortality.

OBJECTIVES This study sought to determine whether the evaluation of the combined presence of coronary artery calcium (CAC) and high-sensitivity C-reactive protein (hsCRP) improves discrimination and stratification of hard coronary events and all-cause mortality in the general population. BACKGROUND Coronary atherosclerosis is a chronic inflammatory disease. Both hsCRP as a measure of inflammation and CAC as a measure of coronary plaque burden have been shown to improve risk appraisal. METHODS Framingham risk variables, hsCRP, and CAC were measured in 3,966 subjects without known coronary artery disease or acute inflammation. After 5 years, incident coronary deaths, nonfatal myocardial infarction, and all-cause mortality were determined. RESULTS CAC and hsCRP independently predicted 91 coronary events (adjusted hazard ratios [HRs]: log(2)(CAC+1) = 1.25 [95% confidence interval (CI): 1.16 to 1.34], p < 0.0001; hsCRP = 1.11 [95% CI: 1.02 to 1.21], p = 0.019) and 130 deaths (adjusted HRs: log(2)(CAC+1) = 1.12 [95% CI: 1.06 to 1.19], p < 0.0001; hsCRP = 1.11 [95% CI: 1.04 to 1.19], p = 0.004). For coronary events, net reclassification improvement (NRI) was 23.8% (p = 0.0007) for CAC and 10.5% (p = 0.026) for hsCRP. Adding CAC to Framingham risk variables and hsCRP further improved discrimination of coronary risk but not vice versa. Among persons without CAC, those with hsCRP >3 mg/l versus <3 mg/l had a significantly higher coronary risk (p = 0.006). For all-cause mortality, integrated discrimination improvement (IDI) was positive when CAC or hsCRP were added to age and sex (+0.51%, p < 0.001 and +0.43%, p = 0.012, respectively). Adjusted HRs in the highest versus lowest category of a risk index derived from established CAC and hsCRP thresholds (i.e., CAC = 100 and hsCRP = 3 mg/l) were 5.92 (95% CI: 3.14 to 11.16) for coronary events and 3.02 (95% CI: 1.82 to 5.01) for all-cause mortality (p < 0.0001 each). The adjusted HR for coronary events in intermediate risk subjects was 6.98 (95% CI: 2.47 to 19.73), p < 0.001. CONCLUSIONS The risk of coronary events and all-cause mortality that is mediated by the presence of coronary atherosclerosis and systemic inflammation can be estimated by CAC and hsCRP. An improvement in coronary risk prediction and discrimination was predominantly driven by CAC, whereas hsCRP appears to have a role especially in persons with very low CAC scores.

The prognostic value of cyclin D1, p53, and MDM2 protein expression in uveal melanoma.

Malignant uveal melanoma is the commonest primary intraocular tumour in adults. It metastasizes frequently and 50% of patients die within 10 years of diagnosis. The expression of cyclin D1, p53, and MDM2 in uveal melanoma and their relationship to metastasis‐free 5‐year survival was determined, in order to investigate whether these proteins help to distinguish those patients with a favourable prognosis from those with a poorer one. Ninety‐six eyes enucleated for uveal melanomas were immunohistochemically analysed for the protein expression of cyclin D1 and related cell‐cycle markers, p53 and MDM2. The evaluation of the specimens was undertaken by two independent pathologists without knowledge of the outcome. Statistical analysis of clinical, morphological, and immunohistological features was performed. A ‘favourable outcome’ was defined as survival of at least 5 years after diagnosis, without metastases (n=57). An ‘unfavourable outcome’ was defined as death from metastases within the first 5 years after diagnosis of uveal melanoma (n=39). Cyclin D1 positivity (>15% positive tumour cells) as well as p53 positivity (>15% positive tumour cells) was associated with an unfavourable outcome (for cyclin D1: odds ratio=4.2, 95% confidence interval 1.5–11.8, p=0.006; for p53: odds ratio=3.2, 95% confidence interval 1.1–9.3, p=0.03). In addition, cyclin D1 positivity was associated with the presence of extraocular extension of the tumour (p=0.01), with the mixed or epithelioid cell type (p=0.02), and with the tumour cell MIB‐1 positivity (p=0.0001). MDM2 immunoreactivity of the tumour cells showed a potential correlation with clinical outcome (odds ratio=2.1, 95% confidence interval 0.8–5.8, p=0.13). Multiple logistic regression models showed that cyclin D1 positivity is an independent prognostic factor after control for other prognostic markers. The expression of cyclin D1 in uveal melanoma is associated with a more aggressive course and histologically unfavourable disease. This could serve as a further independent prognostic factor in uveal melanoma. Copyright

When does work stress hurt? Testing the interaction with socioeconomic position in the Heinz Nixdorf Recall Study

Study objective: To study systematically the separate and combined effects of work stress and socioeconomic position on three measures of health in an unselected working population. Design: Two exposures (high demand/low control (“job strain”); effort–reward imbalance at work) are related to angina pectoris, depression, and poor self-rated health in a cross-sectional study design in which socioeconomic position was measured by occupational position and educational level. Setting: Baseline data of a prospective population-based cohort study in Germany, collected between 2000 and 2003. Participants: 1749 employed or self-employed men and women (36.3% of total sample) aged 45–65 years. Main results: Effort–reward imbalance and job strain were associated with elevated odds ratios of all three health measures, using logistic regression analysis. The prevalence of poorer health was always highest in subgroups defined by high work stress and low socioeconomic position, with respective odds ratios ranging from 2.30 to 2.98 (95% CI 1.38 to 4.52) for self-rated health, 1.70 to 2.24 (95% CI 1.04 to 3.88) for angina and 2.61 to 8.20 (95% CI 1.53 to 14.15) for depression. Conclusion: Although stress at work was related to poorer health in the total study group, the strongest associations were consistently observed in men and women with low educational level or low occupational position. Worksite health promotion should be directed primarily towards these target groups.

Control response proportions in population-based case-control studies in Germany.

We investigated the methods of recruitment, levels and determinants of response, and the calculation method of response proportions in population-based case-control studies in Germany. We identified 26 eligible studies. The pooled analysis showed that the response proportion was 68% among controls and 80% among cases. Response proportions among controls without telephones were about 50% lower than for controls with telephones. We propose a new measure that indicates the efficacy of the recruitment strategy.