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1.  From prescriptions to drug use periods - things to notice 
BMC Research Notes  2014;7(1):796.
Electronic prescription registers provide a vast data source for pharmacoepidemiological research. Prescriptions as such are not suitable for all research purposes; e.g., studying concurrent use of different drugs or adverse drug events during current use. For those purposes, data on dispensed prescriptions needs to be transformed to periods of drug use.
We used 3,828,292 dispensed prescriptions claimed between 1 January 2002 and 31 December 2009 for 28,093 persons with Alzheimer’s disease. Examples of drug use histories are presented to discuss different aspects that should be noticed when using register-based data consisting of drug purchases.
There is no simple method for correctly transforming dispensed prescriptions to periods of drug use that is usable for all drugs and drug users. Fixed assumptions of daily dose (in defined daily doses, tablets or other units) and fixed time windows should be used with caution and adjusted for different drug use patterns.
We recommend that when transforming prescription drug purchases to drug use periods personal dose, purchasing pattern and other behavioral differences between patients should be taken into account.
PMCID: PMC4239374  PMID: 25398553
Prescription register; Modeling; Drug utilization; Pharmacoepidemiology
2.  Genetic Risk for Schizophrenia, Obstetric Complications, and Adolescent School Outcome: Evidence for Gene-Environment Interaction 
Schizophrenia Bulletin  2012;39(5):1067-1076.
Low birth weight (LBW) and hypoxia are among the environmental factors most reliably associated with schizophrenia; however, the nature of this relationship is unclear and both gene-environment interaction and gene-environment covariation models have been proposed as explanations. High-risk (HR) designs that explore whether obstetric complications differentially predict outcomes in offspring at low risk (LR) vs HR for schizophrenia, while accounting for differences in rates of maternal risk factors, may shed light on this question. This study used prospectively obtained data to examine relationships between LBW and hypoxia on school outcome at age 15–16 years in a Finnish sample of 1070 offspring at LR for schizophrenia and 373 offspring at HR for schizophrenia, based on parental psychiatric history. Controlling for offspring sex, maternal smoking, social support, parity, age, and number of prenatal care visits, HR offspring performed worse than LR offspring across academic, nonacademic, and physical education domains. LBW predicted poorer academic and physical education performance in HR offspring, but not in LR offspring, and this association was similar for offspring of fathers vs mothers with schizophrenia. Hypoxia predicted poorer physical education score across risk groups. Rates of LBW and hypoxia were similar for LR and HR offspring and for offspring of fathers vs mothers with schizophrenia. Results support the hypothesis that genetic susceptibility to schizophrenia confers augmented vulnerability of the developing brain to the effects of obstetric complications, possibly via epigenetic mechanisms.
PMCID: PMC3756777  PMID: 22941745
low birth weight; hypoxia; high risk; academic; physical education
3.  Antidementia drug use among community-dwelling individuals with Alzheimer’s disease in Finland: a nationwide register-based study 
The objective of this study was to investigate the prevalence of acetylcholinesterase inhibitor (AChEI) and memantine use, duration of treatment, concomitant use of these drugs, and factors associated with the discontinuation of AChEI therapy during 2006–2009. We utilized data from a nationwide sample of community-dwelling individuals with a clinically verified Alzheimer’s disease diagnosed during the year 2005 (n=6858) as a part of the MEDALZ-2005 study. During the 4-year follow-up, 84% used AChEI and 47% used memantine. Altogether, 22% of the sample used both drugs concomitantly. The median duration of the first AChEI use period was 860 (interquartile range 295–1458) days and 1103 (interquartile range 489–1487) days for the total duration of AChEI use. Although 20% of the AChEI users discontinued the use during the first year, over half of them restarted later. The risk of discontinuation was higher for rivastigmine [hazard ratio 1.34 (confidence interval 1.22–1.48)] and galantamine users [hazard ratio 1.23 (confidence interval 1.15–1.37)] compared with donepezil users in the adjusted model. In conclusion, median time for AChEI use was over 3 years and every fifth Alzheimer’s disease patient used AChEI and memantine concomitantly during the follow-up. The low rate of discontinuation is consistent with the Finnish Care Guideline but in contrast to the results reported from many other countries.
PMCID: PMC4047310  PMID: 24608822
acetylcholinesterase inhibitor; Alzheimer’s disease; drug utilization; memantine; prevalence
4.  Use of existing data sources in clinical epidemiology: Finnish health care registers in Alzheimer’s disease research – the Medication use among persons with Alzheimer’s disease (MEDALZ-2005) study 
Clinical Epidemiology  2013;5:277-285.
Memory diseases are the most important determinant of health care service use and quality of life among older individuals. Adverse effects of medication are common among older people, but this age group is underrepresented in clinical trials. Finnish statutory health care and prescription registers, together with personal identification numbers (PINs) and a tax-supported public health plan covering all citizens provide excellent opportunities for epidemiological research. We used routinely collected data from the Finnish health care system to establish the Medication use among persons with Alzheimer’s disease (MedAlz-2005) cohort. This cohort study will be used to assess medication use and its effects on health status and hospitalization among persons with Alzheimer’s disease (Ad). The cohort includes all community-dwelling persons who had a clinically verified diagnosis of Ad, resided in Finland, and were alive on December 31, 2005 and a matched comparison person for each affected individual. data on purchased prescription medicines (1995–2009), inpatient hospital admissions (1972–2009), outpatient visits (1995–2009), details on diagnosed cancers (1972–2009), and mortality (until October 2010) are available for the whole cohort. This paper describes how this data can be utilized in etiological research and the assessment of health care service use, drug utilization, and associated adverse outcomes in a particularly vulnerable group that is often underrepresented in clinical trials.
PMCID: PMC3741080  PMID: 23950660
drug utilization; pharmacoepidemiology; epidemiology; cohort
5.  The data management of a phase III efficacy trial of an 11-valent pneumococcal conjugate vaccine and related satellite studies conducted in the Philippines 
BMC Research Notes  2012;5:274.
A large phase III placebo-controlled, randomized efficacy trial of an investigational 11-valent pneumococcal conjugate vaccine against pneumonia in children less than 2 years of age was conducted in the Philippines from July 2000 to December 2004. Clinical data from 12,194 children who were given either study vaccine or placebo was collected from birth up to two years of age for the occurrence of radiologically proven pneumonia as the primary endpoint, and for clinical pneumonia and invasive pneumococcal disease as the secondary endpoints. Several tertiary endpoints were also explored. Along the core trial, several satellite studies on herd immunity, cost-effectiveness of the study vaccine, acute otitis media, and wheezing were conducted.
We describe here in detail how the relevant clinical records were managed and how quality control procedures were implemented to ensure that valid data were obtained respectively for the core trial and for the satellite studies. We discuss how the task was achieved, what the challenges were and what might have been done differently.
There were several factors that made the task of data management doable and efficient. First, a pre-trial data management system was available. Secondly, local committed statisticians, programmers and support staff were available and partly familiar to clinical trials. Thirdly, the personnel had undergone training during trial and grew with the task they were supposed to do. Thus the knowledge needed to develop and operate clinical data system was fully transferred to local staff.
Trial registration
Current Controlled Trials ISRCTN62323832
PMCID: PMC3434041  PMID: 22676626
6.  Geographic Information System and tools of spatial analysis in a pneumococcal vaccine trial 
BMC Research Notes  2012;5:51.
The goal of this Geographic Information System (GIS) study was to obtain accurate information on the locations of study subjects, road network and services for research purposes so that the clinical outcomes of interest (e.g., vaccine efficacy, burden of disease, nasopharyngeal colonization and its reduction) could be linked and analyzed at a distance from health centers, hospitals, doctors and other important services. The information on locations can be used to investigate more accurate crowdedness, herd immunity and/or transmission patterns.
A randomized, placebo-controlled, double-blind trial of an 11-valent pneumococcal conjugate vaccine (11PCV) was conducted in Bohol Province in central Philippines, from July 2000 to December 2004. We collected the information on the geographic location of the households (N = 13,208) of study subjects. We also collected a total of 1982 locations of health and other services in the six municipalities and a comprehensive GIS data over the road network in the area.
We calculated the numbers of other study subjects (vaccine and placebo recipients, respectively) within the neighborhood of each study subject. We calculated distances to different services and identified the subjects sharing the same services (calculated by distance). This article shows how to collect a complete GIS data set for human to human transmitted vaccine study in developing country settings in an efficient and economical way.
The collection of geographic locations in intervention trials should become a routine task. The results of public health research may highly depend on spatial relationships among the study subjects and between the study subjects and the environment, both natural and infrastructural.
Trial registration number
PMCID: PMC3298525  PMID: 22264271
7.  Between-Strain Competition in Acquisition and Clearance of Pneumococcal Carriage—Epidemiologic Evidence From a Longitudinal Study of Day-Care Children 
American Journal of Epidemiology  2009;171(2):169-176.
The state of pneumococcal carriage—that is, pneumococcal colonization in the nasopharynx of healthy persons—represents a reservoir for the spread of pneumococci among individuals. In light of the introduction of new pneumococcal conjugate vaccines, further knowledge on the dynamics of pneumococcal carriage is important. Different serotypes (strains) of pneumococcus are known to compete with each other in colonizing human hosts. Understanding the strength and mode of between-serotype competition is important because of its implications for vaccine-induced changes in the ecology of pneumococcal carriage. Competition may work through reduced acquisition of new serotypes, due to concurrent carriage in the individual, or through enhanced clearance of serotypes in carriers who harbor more than 1 serotype simultaneously. The authors employed longitudinal data (1999–2001) on pneumococcal carriage in Danish day-care children to analyze between-serotype competition. The data included observations of carriage in children who had not been vaccinated against pneumococcus, and the level of pneumococcal antibiotic resistance and antibiotic usage in the community was very low. Clearance of any single serotype was not affected by simultaneous carriage of other serotypes. In contrast, acquisition of other serotypes in already-colonized hosts was weak (relative rate of acquisition = 0.09, 95% credible interval: 0.05, 0.15).
PMCID: PMC2800239  PMID: 19969530
child; day care; disease reservoirs; longitudinal studies; models, statistical; Streptococcus pneumoniae
8.  Clustering of serotypes in a longitudinal study of Streptococcus pneumoniae carriage in three day care centres 
Streptococcus pneumoniae (pneumococcus) causes a wide range of clinical manifestations that together constitute a major burden of disease worldwide. The main route of pneumococcal transmission is through asymptomatic colonisation of the nasopharynx. Studies of transmission are currently of general interest because of the impact of the new conjugate-polysaccharide vaccines on nasopharyngeal colonisation (carriage). Here we report the first longitudinal study of pneumococcal carriage that records serotype specific exposure to pneumococci simultaneously within the two most important mixing groups, families and day care facilities.
We followed attendees (N = 59) with their family members (N = 117) and the employees (N = 37) in three Finnish day care centres for 9 months with monthly sampling of nasopharyngeal carriage. Pneumococci were cultured, identified and serotyped by standard methods.
Children in day care constitute a core group of pneumococcal carriage: of the 36 acquisitions of carriage with documented exposure to homologous pneumococci, the attendee had been exposed in her/his day care centre in 35 cases and in the family in 9 cases. Day care children introduce pneumococci to the family: 66% of acquisitions of a new serotype in a family were associated with simultaneous or previous carriage of the same type in the child attending day care. Consequently, pneumococcal transmission was found to take place as micro-epidemics driven by the day care centres. Each of the three day care centres was dominated by a serotype of its own, accounting for 100% of the isolates of that serotype among all samples from the day care attendees.
The transmission of pneumococci is more intense within than across clusters defined by day care facilities. The ensuing micro-epidemic behaviour enhances pneumococcal transmission.
PMCID: PMC2639357  PMID: 19116005
9.  Voltage noise influences action potential duration in cardiac myocytes 
Mathematical biosciences  2006;208(1):125-146.
Stochastic gating of ion channels introduces noise to membrane currents in cardiac muscle cells (myocytes). Since membrane currents drive membrane potential, noise thereby influences action potential duration (APD) in myocytes. To assess the influence of noise on APD, membrane potential is in this study formulated as a stochastic process known as a diffusion process, which describes both the current-voltage relationship and voltage noise. In this framework, the response of APD voltage noise and the dependence of response on the shape of the current-voltage relationship can be characterized analytically. We find that in response to an increase in noise level, action potential in a canine ventricular myocytes is typically prolonged and that distribution of APDs becomes more skewed towards long APDs, which may lead to an increased frequency of early after-depolarization formation. This is a novel mechanism by which voltage noise may influence APD. The results are in good agreement with those obtained from more biophysically-detailed mathematical models, and they suggest that increased voltage noise (due to gating noise) may partially underlie an increased incidence of early after-depolarizations in heart failure.
PMCID: PMC2568901  PMID: 17174348
Action potential duration; Voltage fluctuations; Cardiac left ventricular myocyte; Early after-depolarization; Mathematical modeling
10.  Modeling the Actions of β-Adrenergic Signaling on Excitation–Contraction Coupling Processes 
Activation of the β-adrenergic (β-AR) signaling pathway enhances cardiac function through protein kinase A (PKA)–mediated phosphorylation of target proteins involved in the process of excitation–contraction (EC) coupling. Experimental studies of the effects of β-AR stimulation on EC coupling have yielded complex results, including increased, decreased, or unchanged EC coupling gain. In this study, we extend a previously developed model of the canine ventricular myocyte describing local control of sarcoplasmic reticulum (SR) calcium (Ca2+) release to include the effects of β-AR stimulation. Incorporation of phosphorylation-dependent effects on model membrane currents and Ca2+-cycling proteins yields changes of action potential (AP) and Ca2+ transients in agreement with those measured experimentally in response to the nonspecific β-AR agonist isoproterenol (ISO). The model reproduces experimentally observed alterations in EC coupling gain in response to β-AR agonists and predicts the specific roles of L-type Ca2+ channel (LCC) and SR Ca2+ release channel phosphorylation in altering the amplitude and shape of the EC coupling gain function. The model also indicates that factors that promote mode 2 gating of LCCs, such as β-AR stimulation or activation of the Ca2+/calmodulin-dependent protein kinase II (CaMKII), may increase the probability of occurrence of early after-depolarizations (EADs), due to the random, long-duration opening of LCC gating in mode 2.
PMCID: PMC1201510  PMID: 15201146
calcium channels; beta-adrenergic signaling; phosphorylation; excitation-contraction coupling
11.  High vitamin B12 level and good treatment outcome may be associated in major depressive disorder 
BMC Psychiatry  2003;3:17.
Despite of an increasing body of research the associations between vitamin B12 and folate levels and the treatment outcome in depressive disorders are still unsolved. We therefore conducted this naturalistic prospective follow-up study. Our aim was to determine whether there were any associations between the vitamin B12 and folate level and the six-month treatment outcome in patients with major depressive disorder. Because vitamin B12 and folate deficiency may result in changes in haematological indices, including mean corpuscular volume, red blood cell count and hematocrit, we also examined whether these indices were associated with the treatment outcome.
Haematological indices, erythrocyte folate and serum vitamin B12 levels were determined in 115 outpatients with DSM-III-R major depressive disorder at baseline and serum vitamin B12 level again on six-month follow-up. The 17-item Hamilton Depression Rating Scale was also compiled, respectively. In the statistical analysis we used chi-squared test, Pearson's correlation coefficient, the Student's t-test, analysis of variance (ANOVA), and univariate and multivariate linear regression analysis.
Higher vitamin B12 levels significantly associated with a better outcome. The association between the folate level and treatment outcome was weak and probably not independent. No relationship was found between haematological indices and the six-month outcome.
The vitamin B12 level and the probability of recovery from major depression may be positively associated. Nevertheless, further studies are suggested to confirm this finding.
PMCID: PMC317314  PMID: 14641930

Results 1-11 (11)