Discovering Disease Associations by Integrating Electronic Clinical Data and Medical Literature

Electronic health record (EHR) systems offer an exceptional opportunity for studying many diseases and their associated medical conditions within a population. The increasing number of clinical record entries that have become available electronically provides access to rich, large sets of patients' longitudinal medical information. By integrating and comparing relations found in the EHRs with those already reported in the literature, we are able to verify existing and to identify rare or novel associations. Of particular interest is the identification of rare disease co-morbidities, where the small numbers of diagnosed patients make robust statistical analysis difficult. Here, we introduce ADAMS, an Application for Discovering Disease Associations using Multiple Sources, which contains various statistical and language processing operations. We apply ADAMS to the New York-Presbyterian Hospital's EHR to combine the information from the relational diagnosis tables and textual discharge summaries with those from PubMed and Wikipedia in order to investigate the co-morbidities of the rare diseases Kaposi sarcoma, toxoplasmosis, and Kawasaki disease. In addition to finding well-known characteristics of diseases, ADAMS can identify rare or previously unreported associations. In particular, we report a statistically significant association between Kawasaki disease and diagnosis of autistic disorder

Heart failure – risk factors and the validity of diagnoses

Heart failure (HF) is a global health problem. HF risk factors remain understudied. The roles that diabetes and sodium consumption play in HF remain unknown. Furthermore, the validity of HF diagnoses in the Finnish Hospital Discharge Register (FHDR) has not been thoroughly evaluated. This thesis aims to discover sodiumand diabetes-related HF risk factors, validate FHDR-based HF diagnoses, and investigate if the subtyping of register-based HF diagnoses could be improved through electronic health record (EHR) data mining. A 24-hour urinary sodium excretion (mean 183 mmol/d) was measured from 4,630 individuals to assess the relationship between salt intake and incident HF (Study I). We used data from 3,834 diabetic and 90,177 nondiabetic individuals to evaluate the diabetes status-related differences in risk factors and mediators of HF (Study II). Medical records of 120 HF cases and 120 controls were examined to study the validity of HF diagnoses (Study III). We drew data from 33,983 patients to assess if HF diagnoses could be subtyped more accurately through EHR data mining (Study IV) and validated the mining-based versus clinical subtyping in 100 randomly selected patients. In Study I, we observed that high sodium intake was associated with incident coronary artery disease (CAD) and diabetes, but not HF. In Study II, the risk of HF was 2.7-fold in individuals with diabetes compared to nondiabetic participants. Conventional cardiovascular disease risk factors and biomarkers for cardiac strain, myocardial injury, and inflammation were associated with incident HF in both groups. The strongest mediators of HF in diabetes were the direct effect of diabetes and the indirect effects mediated by obesity, cardiac strain/volume overload, and hyperglycemia. In studies III and IV, HF diagnoses of the FHDR had good predictive values (NPV 0.83, PPV 0.85), even when patients with preexisting heart conditions were used as controls. With additional EHR-mined data, the accuracy of our algorithm to correctly classify individuals into HF subtypes versus clinical assessment was 86 %. The findings in this thesis show that register-based HF is an accurate endpoint and that EHR data mining can improve this accuracy. Our results also elucidate the role of sodium and diabetes as HF risk factors.Sydämen vajaatoiminta: riskitekijät ja diagnoosien validiteetti Sydämen vajaatoiminta on maailmanlaajuinen terveysongelma, jonka riskitekijät ovat osin epäselviä. Suolan käytön yhteyttä ja diabeteksen aiheuttamaa korkeaa riskiä vajaatoimintaan ei ole riittävästi tutkittu. Vajaatoimintadiagnoosien validiteettia Hoitoilmoitusjärjestelmä (HILMO)-sairaalarekisterissä ei tiedetä. Tässä väitöskirjatyössä tutkittiin suolaan ja diabetekseen liittyviä sydämen vajaatoiminnan riskitekijöitä, validoitiin HILMO-pohjaiset vajaatoimintadiagnoosit ja selvitettiin, voidaanko vajaatoimintaa alatyypittää tekstinlouhintaa käyttämällä. Suolan saannin ja vajaatoiminnan välisen suhteen arvioimiseksi (tutkimus I) tutkittiin 4 630 henkilön vuorokausivirtsan natrium (keskimäärin 183 mmol/d). Diabetekseen liittyvien sydämen vajaatoiminnan riskitekijöiden selvittämiseksi (tutkimus II) käytiin läpi 3 834 diabeetikon ja 90 177 verrokin tiedot. Vajaatoimintadiagnoosien validiteettia (tutkimus III) varten tutkimme 120 vajaatoimintatapauksen ja 120 verrokin (joilla oli muu sydänsairaus) potilastiedot ja tarkempaa alatyypitystä (tutkimus IV) varten keräsimme tietoja 33 983 potilaasta ja validoimme tiedonlouhintaan perustuvan alatyypityksen 100 satunnaisella potilaalla. Tutkimuksessa I suolan saanti oli yhteydessä sepelvaltimotaudin ja diabeteksen kehittymiseen, mutta tulokset eivät olleet merkitseviä vajaatoiminnan osalta. Tutkimuksessa II diabeetikoiden vajaatoimintariski oli 2,7-kertainen verrokkeihin verrattuna. Molemmilla tavanomaiset riskitekijät ja sydämen venyvyyden, sydänvaurion ja tulehduksen merkkiaineet olivat yhteydessä vajaatoimintaan. Merkittävimmät diabeteksen vajaatoimintaa välittävät muuttujat olivat diabeteksen suora vaikutus sekä epäsuorat ylipainon, sydämen venymisen ja hyperglykemian vaikutukset. Tutkimuksissa III ja IV HILMO-rekisterin vajaatoimintadiagnoosin prediktiiviset arvot olivat hyviä (NPV 0,83, PPV 0,85) verrattuna muihin sydänsairaisiin potilaihin ja tiedonlouhinnan alatyypityksen tarkkuus verrattuna kliiniseen oli 86 %. Tämä väitöskirja osoittaa, että HILMO-pohjaiset vajaatoimintadiagnoosit toimivat tieteellisenä päätetapahtumana ja että vajaatoiminnan alatyyppiä voidaan tarkentaa tekstilouhinnalla, sekä tuo uutta tietoa suolasta ja diabeteksesta vajaatoiminnan riskitekijöinä

Inhal Toxicol

The effects of acute pulmonary coexposures to silica and diesel particulate matter (DPM), which may occur in various mining operations, were investigated in vivo. Rats were exposed by intratracheal instillation (IT) to silica (50 or 233\ua0\ub5g), DPM (7.89 or 50\ua0\ub5g) or silica and DPM combined in phosphate-buffered saline (PBS) or to PBS alone (control). At one day, one week, one month, two months and three months postexposure bronchoalveolar lavage and histopathology were performed to assess lung injury, inflammation and immune response. While higher doses of silica caused inflammation and injury at all time points, DPM exposure alone did not. DPM (50\ua0\ub5g) combined with silica (233\ua0\ub5g) increased inflammation at one week and one-month postexposure and caused an increase in the incidence of fibrosis at one month compared with exposure to silica alone. To assess susceptibility to lung infection following coexposure, rats were exposed by IT to 233\ua0\ub5g silica, 50\ua0\ub5g DPM, a combination of the two or PBS control one week before intratracheal inoculation with 5\u2009 7\u200910| Listeria monocytogenes. At 1, 3, 5, 7 and 14 days following infection, pulmonary immune response and bacterial clearance from the lung were evaluated. Coexposure to DPM and silica did not alter bacterial clearance from the lung compared to control. Although DPM and silica coexposure did not alter pulmonary susceptibility to infection in this model, the study showed that noninflammatory doses of DPM had the capacity to increase silica-induced lung injury, inflammation and onset/incidence of fibrosis.CC999999/Intramural CDC HHS/United States2019-06-03T00:00:00Z28967277PMC6545482636

Assessment of factors associated with diabetic retinopathy among diabetic patients in Zambia

Background: Diabetes Mellitus is an emerging public health problem in Africa. Evidence suggests that globalization, rapid urbanization and a nutritional transition have led to the rise in the prevalence of diabetes mellitus in Africa. Diabetic retinopathy is a common complication of diabetes mellitus that causes visual impairment and subsequent blindness. Early detection and prompt treatment can prevent blindness in up to 90% of patients. The common risk factors for diabetic retinopathy include hypertension, hyperglycemia and long duration of diabetes. Other risk factors include obesity, hyperlipidemia, smoking, puberty and pregnancy. There is limited data on diabetic retinopathy and its associated risk factors in Zambia. An understanding of these factors would help in the effective management of diabetic retinopathy. Methods: A secondary data analysis of data obtained from a hospital-based cross-sectional study of diabetic patients attending diabetic clinics in the Copperbelt Province in Zambia was carried out. All diabetic patients that attended the retinopathy-screening program between April 2012 and September 2012 were eligible for the primary study. The secondary data analysis was restricted to patients 18 years and older. Data analysis was carried out by R version 3.3.1. The characteristics of the study population were summarized using descriptive statistics. Univariate logistic regression analysis was used to select potential candidates for the multivariate regression model at p-value cutoff point ≤ 0.25 and variables of known clinical relevance were also included in the multivariable analysis. The final model fitness was checked using Hosmer and Lemeshow chi-square test. Finally, statistical significance was tested at P-value <0.05. Results: The prevalence of diabetic retinopathy was 19.4%. Multivariate analysis showed that the odds of diabetic retinopathy were significantly associated with age (OR =1.05: 95%Cl; 1.03-1.06), duration (OR=1.39: 95%Cl; 1.27-1.52), weight (OR =0.98: 95%Cl; 0.97-0.98), blood glucose (OR =1.04: 95Cl; 1.02-1.07) and systolic blood pressure (OR = 1.01: 95Cl; 1.00-1.02). Conclusion: Duration of diabetes, age, systolic blood pressure, weight and blood glucose levels were significantly associated with diabetic retinopathy in this study. More comprehensive population screening strategies and treatment programs addressing these risk factors should be put in place

Primary Health Care

This book presents examples from various countries about the provision of health services at the primary care level. Chapters examine the role of professionals in primary healthcare services and how they can work to improve the health of individuals and communities. Written by authors from Africa, Asia, America, Europe, and Australia, this book provides up-to-date information on primary health care, including telehealth services in the era of COVID-19

Excretion of heavy metals from the biliary tract and its association with pancreato-biliary malignancy

PhD ThesisBiliary and pancreatic cancers are associated with poor prognosis and high mortality. A variety of genetic and environmental factors have been implicated as possible causes of these cancers. New epidemiological studies are looking into the possible role of heavy metals such as lead, chromium, nickel and cadmium as carcinogens. Studies from areas of wide geographical differences such as Egypt, USA and India have reported a possible association of heavy metals such as lead and cadmium with pancreato-biliary malignancy. These studies were from areas of significant environmental pollution with these metals due to the proximity of heavy industry or mining activities. No association has been demonstrated between metal exposure and pancreato-biliary malignancy in areas of low environmental pollution. Aim The aim of this study was to look at a possible association between excretion of heavy metals from the biliary tract and pancreato-biliary malignancy in an industrial area in the North-East of England. Materials and Methods Patients with malignant biliary obstruction admitted to a tertiary referral centre were identified prospectively. Bile was collected either during endoscopic retrograde cholangiography (ERC), percutaneous transhepatic 10 cholangiography (PTC) or during biliary tract surgery. Bile was also collected from patients with benign biliary disease to act as controls. The bile samples were analyzed for concentrations of lead, copper, zinc, cadmium, chromium and nickel using atomic absorption spectrometry after pre-treatment by the acid digestion method. The mean levels of every metal in the study groups (biliary malignancy and pancreatic malignancy) and the control group were compared by using SPSS 16© (SPSS Inc) statistical software. It was uncertain whether there would be a measurable quantity of heavy metals in the bile collected during the above procedures and therefore it was felt necessary to perform a small pilot study to standardize the methods and address any possible difficulties. Results Bile samples collected from 107 patients over a period of 18 months were included in this study. As part of the pilot study two different methods of purification of bile (acid digestion vs syringe filtration) were evaluated and acid digestion was chosen as a more reliable method. For the main study, after exclusion due to inadequate volume of sample, a total of 127 bile samples from 98 patients (43 male, 55 female, median age 65.82 years, range 20-82 years) were analyzed. On final analysis, the malignant group comprised of 3 subgroups: pancreatic cancer, biliary cancer and periampullary cancer. Results from these 3 groups were compared with those from the benign control group. The groups were sex-matched but there was a significant difference in age distribution between the benign and 11 malignant groups (p<0.001). Bile samples were obtained from both gallbladder (GB) and common bile duct (CBD) in 33 patients and from either of these sources in the remainder. There was a strong positive correlation between the concentration of each metal when obtained from either GB or CBD. The main results of this study have shown that copper was present at significantly higher levels in the benign control group (p=0.004) and that cadmium was present at significantly higher levels in the malignant groups (p=0.02). There was no significant difference amongst the groups for the other heavy metals. Discussion Cadmium has been implicated as a possible environmental carcinogen for various malignancies, including pancreatic cancer. Most studies that show this association are from areas of high environmental pollution. The present study supports this association. There is evidence of excess environmental exposure to heavy metals, including cadmium, in the North-East of England. This exposure is mainly in relation to mining activities in the past in this region and is mainly noticed downstream along the rivers draining the areas with significant mining history. The results of this study support the possible association between heavy metal exposure and pancreatic and biliary malignancy. Further research is needed to establish the specific carcinogenic role of heavy metals such as cadmium in pancreato-biliary malignancies

Real-World Evidence in Healthcare Decision Making : Global trends and case studies from Latin America

Objectives: Real-world evidence (RWE) is increasingly used to inform health technology assessments (HTAs) for resource allocation, which are valuable tools for emerging economies such as in America. However, the characteristics and uses in South America are unknown. This study aims to identify sources, characteristics and uses of RWE in Argentina, Brazil, Colombia and Chile, and evaluate the context-specific challenges. The implications for future regulation and responsible management of RWE in the region are also considered. Methods: A systematic literature review, database mapping, and targeted grey literature search were conducted to identify the sources and characteristics of RWE. Findings were validated by key opinion leaders attending workshops in four South American countries. Results: A database mapping exercise revealed 407 unique databases. Geographic scope, database type, population and outcomes captured were reported. Characteristics of National Health Information Systems show efforts to collect interoperable data from service providers, insurers and government agencies, but that initiatives are hampered by fragmentation, lack of stewardship and resources. RWE is mainly used in South America for pharmacovigilance and as pure academic research, but less so for HTA decision-making or pricing negotiations and not at all to inform early access schemes. Conclusions: The quality of data collected in real-world in the case-study countries varies and RWE is not consistently used in healthcare decision-making. Authors recommend that future studies monitor the impact of digitalisation, and the potential effects of access to RWE on the quality of patient care

An In Vivo Evaluation of Pulmonary Immune Response and Toxicity Following Combined Respiratory Exposure to Crystalline Silica and Diesel Particulate Matter

Crystalline silica (SIL) and diesel particulate matter (DPM) are each well-recognized for their potential to cause pulmonary toxicity following inhalation. However, these particulates have also been identified as coexisting in mixtures of respirable aerosols at a variety of industrial settings: mining, oil and gas extraction, construction, road construction, tunneling, excavation, foundry, and sandblasting. In order to characterize the potential for increased pulmonary health effects when these particulates are inhaled in a mixture, a battery of acute and subacute in vivo exposure studies were conducted. The current studies examined co-exposure to SIL and DPM at doses that were derived from field measures collected during industrial activities. The project had three major aims: (1a) Characterize the pulmonary response to an acute co-exposure to DPM and SIL at varying doses; (1b) characterize the pulmonary response to a repeated co-exposure to DPM and SIL in order to determine if subacute exposure vs. acute exposure altered the effects observed for 1a; (2) establish if susceptibility to an acute respiratory infection was altered following a co-exposure of DPM and SIL; and (3) determine whether clearance of particulate in a co-exposure to DPM and SIL was altered compared with the clearance rate of either particle individually to assess the effect of particle load in toxicity. Co-exposure of rats to SIL and DPM had the capability to enhance indicators of inflammation, injury, oxidant production by phagocytes, onset of the initiation of fibrosis, and differentially alter immunological responses when administered in combination, compared to either particle individually. In acute infection models examining respiratory susceptibility following exposure to particles, the highest dose of DPM was shown to suppress bacterial clearance in the innate phase of the immune response as compared to SIL. It was determined that although some macrophage functions were reduced by the presence of DPM early in the time course (1 to 3 days following infection), all groups cleared the infection at a similar rate in the adaptive phase of the immune response. Further, it was determined that some effects in the co-exposure group were associated with the presence of SIL and the overall particle load over time, particularly tissue remodeling and the development of fibrosis; whereas other effects were due to specific characteristics of DPM including inflammation, injury, and oxidant production. Overall, the studies indicate that silica-exposed workers may be at an increased risk for adverse health effects when concomitantly exposed to diesel particulate, even doses that cause low toxicity in individual exposures