Peter R. Rijnbeek

Observational Health Data Sciences and Informatics (OHDSI): Opportunities for Observational Researchers.

The vision of creating accessible, reliable clinical evidence by accessing the clincial experience of hundreds of millions of patients across the globe is a reality. Observational Health Data Sciences and Informatics (OHDSI) has built on learnings from the Observational Medical Outcomes Partnership to turn methods research and insights into a suite of applications and exploration tools that move the field closer to the ultimate goal of generating evidence about all aspects of healthcare to serve the needs of patients, clinicians and all other decision-makers around the world.

Normal limits of the electrocardiogram in Chinese subjects

BACKGROUND Accurate normal limits of the electrocardiogram (ECG) are the basis on which diagnostic criteria are developed. The ECG, however, is subject to age- and sex-variations and may also be racially determined. Studies into normal ECG limits for the Chinese, comprising one fifth of the world population, are few and have their limitations. We have undertaken to establish normal limits of the ECG from a large sample of healthy Chinese subjects. METHODS Standard simultaneous 12-lead ECGs from 5360 apparently healthy Chinese subjects (3614 men and 1746 women, ages ranging from 18 to 84 years) were collected with a modern digital recorder and processed with a well-validated ECG computer program. The medians, lower limits (2nd percentile) and upper limits (98th percentile) of various ECG measurements were calculated and age and sex differences examined. RESULTS Significant age trends were present in, for example, P-wave duration, QTc interval, and frontal QRS axis, with concomitant changes of R amplitudes in the extremity leads. Sex differences existed for heart rate, interval durations, the Sokolow and Cornell indices, and QRS and ST-T amplitudes in different leads. Notably, left-precordial R-wave amplitudes in women increased with age; the Sokolow index showed a clearer age trend for men than for women, the reverse being true for the Cornell index. Some of these findings are at odds with established diagnostic ECG criteria. CONCLUSIONS Normal ECG limits of Chinese subjects show marked age and sex differences. This merits the definition and use of age- and sex-specific ECG criteria for a Chinese population.

Chronic obstructive pulmonary disease and sudden cardiac death: the Rotterdam study

AIMS Both sudden cardiac death (SCD) and chronic obstructive pulmonary disease (COPD) are common conditions in the elderly. Previous studies have identified an association between COPD and cardiovascular disease, and with SCD in specific patient groups. Our aim was to investigate whether there is an association between COPD and SCD in the general population. METHODS AND RESULTS The Rotterdam study is a population-based cohort study among 14 926 subjects aged 45 years and older with up to 24 years of follow-up. Analyses were performed with a (time dependent) Cox proportional hazard model adjusted for age, sex, and smoking. Of the 13 471 persons included in the analysis; 1615 had a diagnosis of COPD and there were 551 cases of SCD. Chronic obstructive pulmonary disease was associated with an increased risk of SCD (age- and sex-adjusted hazard ratio, HR, 1.34, 95% CI 1.06-1.70). The risk particularly increased in the period 2000 days (5.48 years) after the diagnosis of COPD (age- and sex-adjusted HR 2.12, 95% CI 1.60-2.82) and increased further to a more than three-fold higher risk in COPD subjects with frequent exacerbations during this period (age- and sex-adjusted HR 3.58, 95% CI 2.35-5.44). Analyses restricted to persons without prevalent myocardial infarction or heart failure yielded similar results. CONCLUSION Chronic obstructive pulmonary disease is associated with an increased risk for SCD. The risk especially increases in persons with frequent exacerbations 5 years after the diagnosis of COPD. This risk indicator could provide new directions for better-targeted actions to prevent SCD.

Normal values of the electrocardiogram for ages 16-90 years

INTRODUCTION To establish an up-to-date and comprehensive set of normal values for the clinically current measurements in the adult ECG, covering all ages for both sexes. METHODS The study population included 13,354 individuals, taken from four population studies in The Netherlands, ranging in age from 16 to 90 years (55% men) and cardiologically healthy by commonly accepted criteria. Standard 12-lead ECGs were available for all participants. The ECGs were processed by a well-validated computer program. Normal limits were taken as the 2nd and 98th percentiles of the measurement distribution per age group. RESULTS Our study corroborates many findings of previous studies, but also provides more differentiated results, in particular for the older age groups. Age trends were apparent for the QTc interval, QRS axis, and indices of left ventricular hypertrophy. Amplitudes in the left precordial leads showed a substantial increase in the older age groups for women, but not for men. Sex-dependent differences were apparent for most ECG parameters. All results are available on the Website www.normalecg.org, both in tabular and in graphical format. CONCLUSIONS We determined age- and sex-dependent normal values of the adult ECG. Our study distinguishes itself from other studies by the large size of the study population, comprising both sexes, the broad range of ages, and the exhaustive set of measurements. Our results emphasize that most diagnostic ECG criteria should be age- and sex-specific.

Electrocardiographic Criteria for Left Ventricular Hypertrophy in Children

Previous studies to determine the sensitivity of the electrocardiogram (ECG) for left ventricular hypertrophy (LVH) in children had their imperfections: they were not done on an unselected hospital population, several criteria used in adults were not applied to children, and obsolete limits of normal for the ECG parameters were used. Furthermore, left ventricular mass (LVM) was taken as the reference standard for LVH, with no regard for other clinical evidence. The study population consisted of 832 children from whom a 12-lead ECG and an M-mode echocardiogram were taken on the same day. The validity of the ECG criteria was judged on the basis of an abnormal LVM index, either alone or in combination with other clinical evidence. The ECG criteria were based on recently established age-dependent normal limits. At 95% specificity, the ECG criteria have low sensitivities (<25%) when an elevated LVM index is taken as the reference for LVH. When clinical evidence is also taken into account, the sensitivity improved considerably (<43%). Sensitivities could be further improved when ECG parameters were combined. The sensitivity of the pediatric ECG in detecting LVH is low but depends strongly on the definition of the reference used for validation.

Effects of fluticasone propionate on methacholine dose-response curves in nonsmoking atopic asthmatics

Methacholine is frequently used to determine bronchial hyperresponsiveness (BHR) and to generate dose-response curves. These curves are characterized by a threshold (provocative concentration of methacholine producing a 20% fall in forced expiratory volume in one second (PC20) = sensitivity), slope (reactivity) and maximal response (plateau). We investigated the efficacy of 12 weeks of treatment with 1,000 microg fluticasone propionate in a double-blind, placebo-controlled study in 33 atopic asthmatics. The outcome measures used were the influence on BHR and the different indices of the methacholine dose-response (MDR) curve. After 2 weeks run-in, baseline lung function data were obtained and a MDR curve was measured with doubling concentrations of the methacholine from 0.03 to 256 mg x mL(-1). MDR curves were repeated after 6 and 12 weeks. A recently developed, sigmoid cumulative Gaussian distribution function was fitted to the data. Although sensitivity was obtained by linear interpolation of two successive log2 concentrations, reactivity, plateau and the effective concentration at 50% of the plateau value (EC50) were obtained as best fit parameters. In the fluticasone group, significant changes occurred after 6 weeks with respect to means of PC20 (an increase of 3.4 doubling doses), plateau value fall in forced expiratory volume in one second (FEV1) (from 58% at randomization to 41% at 6 weeks) and baseline FEV1 (from 3.46 to 3.75 L) in contrast to the placebo group. Stabilization occurred after 12 weeks. Changes for reactivity were less marked, whereas changes in log, EC50 were not significantly different between the groups. We conclude that fluticasone is very effective in decreasing the maximal airway narrowing response and in increasing PC20. However, it is likely that part of this increase is related to the decrease of the plateau of maximal response.

Declining incidence of sudden cardiac death from 1990-2010 in a general middle-aged and elderly population: The Rotterdam Study

BACKGROUND Although sudden cardiac death (SCD) is relatively common, contemporary data on its incidence are lacking. OBJECTIVE The purpose of this study was to investigate the current incidence of SCD and its trend over the past 2 decades in a general middle-aged and elderly population. METHODS This study was performed within the Rotterdam Study, a prospective population-based cohort study of persons aged 45 years and older. Age-standardized incidence rates of SCD were calculated. To study trends in incidence, we compared 2 subcohorts within the total study population, 1 followed from 1990-2000 and the other from 2001-2010. RESULTS From 1990-2010, 5512 of 14,628 participants died, of whom 583 (4.0%) were classified as SCD. The overall incidence was 4.2 per 1000 person-years. The incidence was higher in men (5.2 per 1000 person-years) than in women (3.6 per 1000 person-years). Age-adjusted hazard ratio (HR) 1.84 (95% confidence [CI] 1.56-2.17) and risk of SCD increased with age (HR 1.10 per year; 95% CI 1.09-1.11). The incidence rate from 1990-2000 was 4.7 per 1000 person-years vs 2.1 per 1000 person-years from 2001-2010 (age- and sex-adjusted HR of SCD 0.60, 95% CI 0.44-0.80). To check for cohort effects, we also analyzed the incidence of total mortality and found an age- and sex-adjusted HR of total mortality of 0.82 (95% CI 0.75-0.90) for the second compared to the first subcohort, which was significantly higher than the decline in SCD incidence. CONCLUSION We found an incidence of SCD of 4.2 per 1000 person-years. The incidence decreased from 1990-2010, a period during which the diagnosis and treatment of heart disease greatly improved.

Pharmacogenetics of Drug-Induced QT Interval Prolongation: An Update

A prolonged QT interval is an important risk factor for ventricular arrhythmias and sudden cardiac death. QT prolongation can be caused by drugs. There are multiple risk factors for drug-induced QT prolongation, including genetic variation. QT prolongation is one of the most common reasons for withdrawal of drugs from the market, despite the fact that these drugs may be beneficial for certain patients and not harmful in every patient. Identifying genetic variants associated with drug-induced QT prolongation might add to tailored pharmacotherapy and prevent beneficial drugs from being withdrawn unnecessarily. In this review, our objective was to provide an overview of the genetic background of drug-induced QT prolongation, distinguishing pharmacokinetic and pharmacodynamic pathways. Pharmacokinetic-mediated genetic susceptibility is mainly characterized by variation in genes encoding drug-metabolizing cytochrome P450 enzymes or drug transporters. For instance, the P-glycoprotein drug transporter plays a role in the pharmacokinetic susceptibility of drug-induced QT prolongation. The pharmacodynamic component of genetic susceptibility is mainly characterized by genes known to be associated with QT interval duration in the general population and genes in which the causal mutations of congenital long QT syndromes are located. Ethnicity influences susceptibility to drug-induced QT interval prolongation, with Caucasians being more sensitive than other ethnicities. Research on the association between pharmacogenetic interactions and clinical endpoints such as sudden cardiac death is still limited. Future studies in this area could enable us to determine the risk of arrhythmias more adequately in clinical practice.

Short-term QT variability markers for the prediction of ventricular arrhythmias and sudden cardiac death: a systematic review

Sudden cardiac death (SCD) is a major health burden and is primarily caused by ventricular arrhythmias. Currently, the most well-known marker for the risk of ventricular arrhythmias is QT/QTc prolongation. Animal studies indicate that QT variability might be a better indicator. Our objective was to give an overview of the literature on QT variability in humans, therefore we performed a free-text search in PubMed and Embase from inception through February 2013. We identified nine QT variability markers in 109 studies reporting on QT variability markers, measured on the surface ECG. QT variability can be distinguished using two characteristics: heart rate normalisation and whether QT interval is measured on consecutive beats. Most study populations were small (median 48 subjects, range 1–805) and different methods, time intervals and leads for measurement were used. QT variability markers were determinants for the risk of ventricular arrhythmias, (sudden) cardiac death and total mortality. Few studies compared the predictive value of QT variability with that of QT/QTc prolongation. A study comparing all different QT variability markers is lacking. In conclusion, QT variability markers are potential determinants of ventricular arrhythmias and cardiac mortality. However, it is unclear which marker and methodology are clinically most useful as well as what reference values are reliable. More studies on larger datasets are needed to find the most accurate marker for the prediction of arrhythmias and SCD to assess its value in addition to QT/QTc duration and its role in drug-induced arrhythmia and sudden death.

Finding a short and accurate decision rule in disjunctive normal form by exhaustive search

Greedy approaches suffer from a restricted search space which could lead to suboptimal classifiers in terms of performance and classifier size. This study discusses exhaustive search as an alternative to greedy search for learning short and accurate decision rules. The Exhaustive Procedure for LOgic-Rule Extraction (EXPLORE) algorithm is presented, to induce decision rules in disjunctive normal form (DNF) in a systematic and efficient manner. We propose a method based on subsumption to reduce the number of values considered for instantiation in the literals, by taking into account the relational operator without loss of performance. Furthermore, we describe a branch-and-bound approach that makes optimal use of user-defined performance constraints. To improve the generalizability we use a validation set to determine the optimal length of the DNF rule. The performance and size of the DNF rules induced by EXPLORE are compared to those of eight well-known rule learners. Our results show that an exhaustive approach to rule learning in DNF results in significantly smaller classifiers than those of the other rule learners, while securing comparable or even better performance. Clearly, exhaustive search is computer-intensive and may not always be feasible. Nevertheless, based on this study, we believe that exhaustive search should be considered an alternative for greedy search in many problems.