Knowledge-based best of breed approach for automated detection of clinical events based on German free text digital hospital discharge letters

OBJECTIVES: The secondary use of medical data contained in electronic medical records, such as hospital discharge letters, is a valuable resource for the improvement of clinical care (e.g. in terms of medication safety) or for research purposes. However, the automated processing and analysis of medical free text still poses a huge challenge to available natural language processing (NLP) systems. The aim of this study was to implement a knowledge-based best of breed approach, combining a terminology server with integrated ontology, a NLP pipeline and a rules engine. METHODS: We tested the performance of this approach in a use case. The clinical event of interest was the particular drug-disease interaction "proton-pump inhibitor [PPI] use and osteoporosis". Cases were to be identified based on free text digital discharge letters as source of information. Automated detection was validated against a gold standard. RESULTS: Precision of recognition of osteoporosis was 94.19%, and recall was 97.45%. PPIs were detected with 100% precision and 97.97% recall. The F-score for the detection of the given drug-disease-interaction was 96,13%. CONCLUSION: We could show that our approach of combining a NLP pipeline, a terminology server, and a rules engine for the purpose of automated detection of clinical events such as drug-disease interactions from free text digital hospital discharge letters was effective. There is huge potential for the implementation in clinical and research contexts, as this approach enables analyses of very high numbers of medical free text documents within a short time period

Exploring the Relationship of Relative Telomere Length and the Epigenetic Clock in the LipidCardio Cohort

Telomere length has been accepted widely as a biomarker of aging. Recently, a novel candidate biomarker has been suggested to predict an individual’s chronological age with high accuracy: The epigenetic clock is based on the weighted DNA methylation (DNAm) fraction of a number of cytosine-phosphate-guanine sites (CpGs) selected by penalized regression analysis. Here, an established methylation-sensitive single nucleotide primer extension method was adapted, to estimate the epigenetic age of the 1005 participants of the LipidCardio Study, a patient cohort characterised by high prevalence of cardiovascular disease, based on a seven CpGs epigenetic clock. Furthermore, we measured relative leukocyte telomere length (rLTL) to assess the relationship between the established and the promising new measure of biological age. Both rLTL (0.79 ± 0.14) and DNAm age (69.67 ± 7.27 years) were available for 773 subjects (31.6% female; mean chronological age= 69.68 ± 11.01 years; mean DNAm age acceleration = −0.01 ± 7.83 years). While we detected a significant correlation between chronological age and DNAm age (n = 779, R = 0.69), we found neither evidence of an association between rLTL and the DNAm age (β = 3.00, p = 0.18) nor rLTL and the DNAm age acceleration (β = 2.76, p = 0.22) in the studied cohort, suggesting that DNAm age and rLTL measure different aspects of biological age

Potential of prevention strategies for the modifiable risk factor type 2 diabetes with relation to the future number of dementia patients in Germany– a multi-state projection through 2040

Background: We assess the impact of prevention strategies regarding type 2 diabetes as a modifiable risk factor for dementia and its consequences for the future number of dementia patients in Germany. Methods: We used a random sample of health claims data (N = 250,000) of insured persons aged 50+ drawn in 2014, and data on population size and death rates in 2015 from the Human Mortality Database. Using exponential hazard models, we calculated age- and sex-specific transition probabilities and death rates between the states (no diabetes/no dementia, diabetes/no dementia, no diabetes/dementia, diabetes/dementia). In multi-state projections, we estimated the future number of dementia cases aged 75+ through 2040 depending on the development of the incidence of diabetes among persons without diabetes and without dementia, and the dementia incidence among persons with and without diabetes. Results: In 2015 there were 1.53 million people with dementia aged 75+ in Germany. A relative annual reduction in death rates of 2.5% and in dementia incidence in persons without diabetes of 1% will increase this number to 3.38 million by 2040. A relative reduction of diabetes incidence by 1% annually would decrease dementia cases by around 30,000, while a reduction of dementia incidence among people with diabetes by 1% would result in 220,000 fewer dementia cases. Both prevention strategies combined would prevent 240,000 dementia cases in 2040. Conclusions: The increase in life expectancy is decisive for the future number of people with dementia. Strategies of better diabetes treatment have the potential to lower the increase in the number of dementia patients in the coming decades.Peer Reviewe

Long-term gait measurements in daily life: Results from the Berlin Aging Study II (BASE-II)

BACKGROUND: Walking ability is an important prerequisite for activity, social participation and independent living. While in most healthy adults, this ability can be assumed as given, limitations in walking ability occur with increasing age. Furthermore, slow walking speed is linked to several chronic conditions and overall morbidity. Measurements of gait parameters can be used as a proxy to detect functional decline and onset of chronic conditions. Up to now, gait characteristics used for this purpose are measured in standardized laboratory settings. There is some evidence, however, that long-term measurements of gait parameters in the living environment have some advantages over short-term laboratory measurements. METHODS: We evaluated cross-sectional data from an accelerometric sensor worn in a subgroup of 554 participants of the Berlin Aging Study II (BASE-II). Data from the two BASE-II age groups (age between 22-36 years and 60-79 years) were used for the current analysis of accelerometric data for a minimum of two days and a maximum of ten days were available. Real world walking speed, number of steps, maximum coherent distance and total distance were derived as average data per day. Linear regression analyses were performed on the different gait parameters in order to identify significant determinants. Additionally, Mann-Whitney-U-tests were performed to detect sex-specific differences. RESULTS: Age showed to be significantly associated with real world walking speed and with the total distance covered per day, while BMI contributed negatively to the number of walking steps, maximum coherent distance and total distance walked. Additionally, sex was associated with walking steps. However, R2-values for all models were low. Overall, women had significantly more walking steps and a larger coherent distance per day when compared to men. When separated by age group, this difference was significant only in the older participants. Additionally, walking speed was significantly higher in women compared to men in the subgroup of older people. CONCLUSIONS: Age- and sex-specific differences have to be considered when objective gait parameters are measured, e.g. in the context of clinical risk assessment. For this purpose normative data, differentiating for age and sex would have to be established to allow reliable classification of long-term measurements of gait

Clinical outcome of a patient with lysosomal acid lipase deficiency and first results after initiation of treatment with Sebelipase alfa: A case report

We report on a case of very rare autosomal recessive cholesteryl ester storage disease due to lysosomal acid lipase deficiency (LALD). LALD is caused by mutations in the lysosomal acid lipase A (LIPA) gene resulting in cholesteryl ester accumulation in liver, spleen, and macrophages. It can lead to liver failure, accelerated atherosclerosis and premature death. Until recently, treatment options were limited to lipid-lowering medications to control dyslipidemia. Presently, a long-term enzyme replacement therapy with Sebelipase alfa, a recombinant human lysosomal acid lipase, is available for patients with LALD. Our patient's condition became conspicuous at the age of two due to a xanthogranuloma of the chin together with increased lipid levels, elevated liver enzymes and hepatomegaly. It took another five years until our patient was diagnosed with LALD after genetic testing. A bi-weekly therapy with intravenous Sebelipase alfa was started at the age of 26 years. It led to normalization of lipid levels, reduction of liver enzymes and beginning regression of hepatomegaly in the absence of adverse drug reactions after 46 infusions. Since LALD can take a fatal course even in patients with a long-term stable condition, it is essential to identify affected patients early and to treat them appropriately by enzyme replacement therapy. LALD should be suspected in patients with low high-density lipoprotein cholesterol (HDL-C) and high low-density lipoprotein cholesterol (LDL-C) in conjunction with elevated liver enzymes or hepatomegaly. A registry for LALD patients shall help to advance our understanding of the disease as well as improve patient care (NCT01633489)

Seven-CpG DNA Methylation Age Determined by Single Nucleotide Primer Extension and Illumina’s Infinium MethylationEPIC Array Provide Highly Comparable Results

DNA methylation age (DNAm age, epigenetic clock) is a novel and promising biomarker of aging. It is calculated from the methylation fraction of specific cytosine phosphate guanine sites (CpG sites) of genomic DNA. Several groups have proposed epigenetic clock algorithms and these differ mostly regarding the number and location of the CpG sites considered and the method used to assess the methylation status. Most epigenetic clocks are based on a large number of CpGs, e.g. as measured by DNAm microarrays. We have recently evaluated an epigenetic clock based on the methylation fraction of seven CpGs that were determined by methylation-sensitive single nucleotide primer extension (MS-SNuPE). This method is more cost-effective when compared to array-based technologies as only a few CpGs need to be examined. However, there is only little data on the correspondence in epigenetic age estimation using the 7-CpG clock and other algorithms. To bridge this gap, in this study we measured the 7-CpG DNAm age using two methods, via MS-SNuPE and via the MethylationEPIC array, in a sample of 1,058 participants of the Berlin Aging Study II (BASE-II), assessed as part of the GendAge study. On average, participants were 75.6 years old (SD: 3.7, age range: 64.9–90.0, 52.6% female). Agreement between methods was assessed by Bland-Altman plots. DNAm age was highly correlated between methods (Pearson’s r = 0.9) and Bland-Altman plots showed a difference of 3.1 years. DNAm age by the 7-CpG formula was 71.2 years (SD: 6.9 years, SNuPE) and 68.1 years (SD: 6.4 years, EPIC array). The mean of difference in methylation fraction between methods for the seven individual CpG sites was between 0.7 and 13 percent. To allow direct conversion of DNAm age obtained from both methods we developed an adjustment formula with a randomly selected training set of 529 participants using linear regression. After conversion of the Illumina data in a second and independent validation set, the adjusted DNAm age was 71.44 years (SD: 6.1 years, n = 529). In summary, we found the results of DNAm clocks to be highly comparable. Furthermore, we developed an adjustment formula that allows for direct conversion of DNAm age estimates between methods and enables one singular clock to be used in studies that employ either the Illumina or the SNuPE method

Low muscle strength and increased arterial stiffness go hand in hand

Low handgrip strength and increased arterial stiffness are both associated with poor health outcomes, but evidence on the relationship between handgrip strength and arterial stiffness is limited. In this cross-sectional analysis of combined baseline datasets from the LipidCardio and Berlin Aging Study II cohorts we aimed to examine whether handgrip strength (HGS) is associated with arterial stiffness. 1511 participants with a median age of 68.56 (IQR 63.13-73.08) years were included. Arterial stiffness was assessed by aortal pulse wave velocity (PWV) with the Mobil-O-Graph device. Handgrip strength was assessed with a handheld dynamometer.The mean HGS was 39.05 +/- 9.07 kg in men and 26.20 +/- 7.47 kg in women. According to multivariable linear regression analysis per 5 kg decrease in handgrip strength there was a mean increase in PWV of 0.08 m/s after adjustment for the confounders age, sex, coronary artery disease, systolic blood pressure, body mass index, cohort, and smoking. Thus, there was evidence that low handgrip strength and increased arterial stiffness go hand in hand. Arterial stiffness can possibly create the missing link between low handgrip strength and increased cardiovascular morbidity and mortality. Causality and direction of causality remain to be determined

Vitamin D insufficiency is associated with metabolic syndrome independent of insulin resistance and obesity in young adults ‐ The Berlin Aging Study II

Purpose: Age-related changes affect vitamin D absorption and metabolism. Low 25-hydroxyvitamin D concentrations have been reported as risk factor for the development of metabolic syndrome (MetS). However, recent evaluations suggest this association might be explained by obesity or insulin resistance (IR) in subjects with MetS. Our aim was to analyze associations between vitamin D insufficiency and MetS in a young cohort without diabetes and two senior cohorts with and without diabetes. Methods: Four hundred sixteen young and 1357 older BASE-II participants were analyzed. Type 2 diabetes (T2D) was defined according to European Society of Cardiology (ESC) guidelines, MetS as suggested by International Diabetes Federation/American Heart Association/National Heart, Lung and Blood Institute (IDF/AHA/NHLBI 2009). Vitamin D insufficiency was defined as 25-hydroxyvitamin D concentrations <50 nmol/L. Among other confounders, BMI and IR were taken into account. Results: MetS was prevalent in 7.7% of the young and in 35.6% of the older BASE-II participants and T2D occurred in 12.7% of the older participants. In young subjects without diabetes, vitamin D insufficiency was associated with an independent 3.2-fold increased odds of having MetS (OR: 3.2 CI: 1.0-8.7; p = 0.042). However, in the older participants, this association was lost once BMI was taken into account among those with diabetes, and once IR was taken into account among those without diabetes. Conclusion: Independent associations between vitamin D insufficiency and MetS were only found among young subjects without diabetes. In the older adults, BMI annihilated these associations among subjects without diabetes as did HOMA-IR among subjects with diabetes

Low-density lipoprotein cholesterol goal attainment in patients with clinical evidence of familial hypercholesterolemia and elevated Lp(a)

Background: Although potent lipid-lowering therapies are available, patients commonly fall short of recommended low-density lipoprotein cholesterol (LDL-C) levels. The aim of this study was to examine the relationship between familial hypercholesterolemia (FH) and elevated lipoprotein(a) [Lp(a)] and LDL-C goal attainment, as well as the prevalence and severity of coronary artery disease (CAD). Moreover, we characterized patients failing to meet recommended LDL-C goals. Methods: We performed a cross-sectional analysis in a cohort of patients undergoing cardiac catheterization. Clinical FH was determined by the Dutch Clinical Lipid Network Score, and Lp(a) >= 50 mg/dL (approximate to 107 nmol/L) was considered elevated. Results: A total of 838 participants were included. Overall, the prevalence of CAD was 72%, and 62% received lipid-lowering treatment. The prevalence of clinical FH (probable and definite FH) was 4%, and 19% had elevated Lp(a) levels. With 35%, LDL-C goal attainment was generally poor. Among the participants with clinical FH, none reached their LDL-C target. Among patients with elevated Lp(a), LDL-C target achievement was only 28%. The prevalence and severity of CAD were higher in participants with clinical FH (86% prevalence) and elevated Lp(a) (80% prevalence). Conclusion: Most participants failed to meet their individual LDL-C goals according to the ESC 2016 and 2019 guidelines. In particular, high-risk patients with clinical FH or elevated Lp(a) rarely met their target for LDL-C. The identification of these patients and more intense treatment approaches are crucial for the improvement of CAD primary and secondary prevention

DNA Damage in Nijmegen Breakage Syndrome Cells Leads to PARP Hyperactivation and Increased Oxidative Stress

Nijmegen Breakage Syndrome (NBS), an autosomal recessive genetic instability syndrome, is caused by hypomorphic mutation of the NBN gene, which codes for the protein nibrin. Nibrin is an integral member of the MRE11/RAD50/NBN (MRN) complex essential for processing DNA double-strand breaks. Cardinal features of NBS are immunodeficiency and an extremely high incidence of hematological malignancies. Recent studies in conditional null mutant mice have indicated disturbances in redox homeostasis due to impaired DSB processing. Clearly this could contribute to DNA damage, chromosomal instability, and cancer occurrence. Here we show, in the complete absence of nibrin in null mutant mouse cells, high levels of reactive oxygen species several hours after exposure to a mutagen. We show further that NBS patient cells, which unlike mouse null mutant cells have a truncated nibrin protein, also have high levels of reactive oxygen after DNA damage and that this increased oxidative stress is caused by depletion of NAD+ due to hyperactivation of the strand-break sensor, Poly(ADP-ribose) polymerase. Both hyperactivation of Poly(ADP-ribose) polymerase and increased ROS levels were reversed by use of a specific Poly(ADP-ribose) polymerase inhibitor. The extremely high incidence of malignancy among NBS patients is the result of the combination of a primary DSB repair deficiency with secondary oxidative DNA damage