Research data warehouse: using electronic health records to conduct population-based observational studies.

Background: Electronic health records and many legacy systems contain rich longitudinal data that can be used for research; however, they typically are not readily available. Materials and methods: At Kaiser Permanente Southern California (KPSC), a research data warehouse (RDW) has been developed and maintained since the late 1990s and widely extended in 2006, aggregating and standardizing data collected from internal and a few external sources. This article provides a high-level overview of the RDW and discusses challenges common to data warehouses or repositories for research use. To demonstrate the application of the data, we report the volume, patient characteristics, and age-adjusted prevalence of selected medical conditions and utilization rates of selected medical procedures. Results: A total of 105 million person-years of health plan enrollment was recorded in the RDW between 1981 and 2018, with most healthcare utilization data available since early or middle 1990s. Among active enrollees on December 31, 2018, 15% were ≥65 years of age, 33.9% were non-Hispanic white, 43.3% Hispanic, 11.0% Asian, and 8.4% African American, and 34.4% of children (2-17 years old) and 72.1% of adults (≥18 years old) were overweight or obese. The age-adjusted prevalence of asthma, atrial fibrillation, diabetes mellitus, hypercholesteremia, and hypertension increased between 2001 and 2018. Hospitalization and Emergency Department (ED) visit rates appeared lower, and office visit rates seemed higher at KPSC compared to the reported US averages. Discussion and conclusion: Although the RDW is unique to KPSC, its methodologies and experience may provide useful insights for researchers of other healthcare systems worldwide in the era of big data analysis.

Inactive USP14 and inactive UCHL5 cause accumulation of distinct ubiquitinated proteins in mammalian cells.

USP14 is a cysteine protease deubiquitinase associated with the proteasome and plays important catalytic and allosteric roles in proteasomal degradation. USP14 inhibition has been considered a therapeutic strategy for accelerating degradation of aggregation-prone proteins in neurodegenerative diseases and for inhibiting proteasome function to induce apoptotic cell death in cancers. Here we studied the effects of USP14 inhibition in mammalian cells using small molecule inhibitors and an inactive USP14 mutant C114A. Neither the inhibitors nor USP14 C114A showed consistent or significant effects on the level of TDP-43, tau or α-synuclein in HEK293T cells. However, USP14 C114A led to a robust accumulation of ubiquitinated proteins, which were isolated by ubiquitin immunoprecipitation and identified by mass spectrometry. Among these proteins we confirmed that ubiquitinated ß-catenin accumulated in the cells expressing USP14 C114A with immunoblotting and immunoprecipitation experiments. The proteasome binding domain of USP14 C114A is required for its effect on ubiquitinated proteins. UCHL5 is the other cysteine protease deubiquitinase associated with the proteasome. Interestingly, the inactive mutant of UCHL5 C88A also caused an accumulation of ubiquitinated proteins in HEK293T cells but did not affect ß-catenin, demonstrating USP14 but not UCHL5 has a specific effect on ß-catenin. We used ubiquitin immunoprecipitation and mass spectrometry to identify the accumulated ubiquitinated proteins in UCHL5 C88A expressing cells which are mostly distinct from those identified in USP14 C114A expressing cells. Among the identified proteins are well established proteasome substrates and proteasome subunits. Besides ß-catenin, we also verified with immunoblotting that UCHL5 C88A inhibits its own deubiquitination and USP14 C114A inhibits deubiquitination of two proteasomal subunits PSMC1 and PSMD4. Together our data suggest that USP14 and UCHL5 can deubiquitinate distinct substrates at the proteasome and regulate the ubiquitination of the proteasome itself which is tightly linked to its function.

Vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases.

IMPORTANCE: Because vaccinations are common, even a small increased risk of multiple sclerosis (MS) or other acquired central nervous system demyelinating syndromes (CNS ADS) could have a significant effect on public health. OBJECTIVE: To determine whether vaccines, particularly those for hepatitis B (HepB) and human papillomavirus (HPV), increase the risk of MS or other CNS ADS. DESIGN, SETTING, AND PARTICIPANTS: A nested case-control study was conducted using data obtained from the complete electronic health records of Kaiser Permanente Southern California (KPSC) members. Cases were identified through the KPSC CNS ADS cohort between 2008 and 2011, which included extensive review of medical records by an MS specialist. Five controls per case were matched on age, sex, and zip code. EXPOSURES: Vaccination of any type (particularly HepB and HPV) identified through the electronic vaccination records system. MAIN OUTCOMES AND MEASURES: All forms of CNS ADS were analyzed using conditional logistic regression adjusted for race/ethnicity, health care utilization, comorbid diseases, and infectious illnesses before symptom onset. RESULTS: We identified 780 incident cases of CNS ADS and 3885 controls; 92 cases and 459 controls were females aged 9 to 26 years, which is the indicated age range for HPV vaccination. There were no associations between HepB vaccination (odds ratio [OR], 1.12; 95% CI, 0.72-1.73), HPV vaccination (OR, 1.05; 95% CI, 0.62-1.78), or any vaccination (OR, 1.03; 95% CI, 0.86-1.22) and the risk of CNS ADS up to 3 years later. Vaccination of any type was associated with an increased risk of CNS ADS onset within the first 30 days after vaccination only in younger (<50 years) individuals (OR, 2.32; 95% CI, 1.18-4.57). CONCLUSIONS AND RELEVANCE: We found no longer-term association of vaccines with MS or any other CNS ADS, which argues against a causal association. The short-term increase in risk suggests that vaccines may accelerate the transition from subclinical to overt autoimmunity in patients with existing disease. Our findings support clinical anecdotes of CNS ADS symptom onset shortly after vaccination but do not suggest a need for a change in vaccine policy.

Prevalence of polycystic ovary syndrome in adolescents.

OBJECTIVE: To investigate the prevalence of polycystic ovary syndrome (PCOS) in adolescents and its association with obesity. DESIGN: Cross-sectional study using electronic medical records. SETTING: Not applicable. PATIENT(S): Adolescents aged 15-19 years (n = 137,502). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): PCOS diagnosed or defined according to National Institutes of Health (NIH) criteria. RESULT(S): The prevalence of a confirmed diagnosis of PCOS was 0.56%, which increased to 1.14% when undiagnosed cases with documented symptoms qualifying for PCOS according to NIH criteria were included. Compared with normal/underweight girls, the odds ratios (OR and 95% confidence interval [CI]) for confirmed PCOS diagnosis were 3.85 (3.04-4.88), 10.25 (8.16-12.84), and 23.10 (18.66-28.61) for overweight, moderately obese, and extremely obese adolescents, respectively, after adjusting for potential confounders. When adolescents with two or more supportive diagnoses were included (diagnosed and undiagnosed PCOS-NIH), the ORs (95% CI) for PCOS-NIH by weight class were significantly attenuated to 2.95 (2.53-3.44), 6.73 (5.78-7.83), and 14.65 (12.73-16.86) for overweight, moderately obese, and extremely obese adolescents, respectively. CONCLUSION(S): Overweight and obesity were associated with higher odds of PCOS in adolescents. Studies based solely on diagnosis codes may underestimate the prevalence of PCOS and overestimate the magnitude of the association between obesity and PCOS.

Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study.

OBJECTIVE: To examine the risk of clinical coronary heart disease (CHD) in patients with rheumatoid arthritis (RA) compared with age- and sex-matched non-RA subjects, and to determine whether RA is a risk factor for CHD after accounting for traditional CHD risk factors. METHODS: We assembled a population-based incidence cohort of 603 Rochester, Minnesota residents ages >or=18 years who first fulfilled the American College of Rheumatology (ACR) 1987 criteria for RA between January 1, 1955 and January 1, 1995, and 603 age- and sex-matched non-RA subjects. All subjects were followed up through their complete inpatient and outpatient medical records, beginning at age 18 years until death, migration, or January 1, 2001. Data were collected on CHD events and traditional CHD risk factors (diabetes mellitus, hypertension, dyslipidemia, body mass index, smoking) using established diagnostic criteria. CHD events included hospitalized myocardial infarction (MI), unrecognized MI, coronary revascularization procedures, angina pectoris, and sudden CHD deaths. Conditional logistic regression and Cox regression models were used to estimate the risk of CHD associated with RA, both prior to and following RA diagnosis, after adjusting for CHD risk factors. RESULTS: During the 2-year period immediately prior to fulfillment of the ACR criteria, RA patients were significantly more likely to have been hospitalized for acute MI (odds ratio [OR] 3.17, 95% confidence interval [95% CI] 1.16-8.68) or to have experienced unrecognized MIs (OR 5.86, 95% CI 1.29-26.64), and less likely to have a history of angina pectoris (OR 0.58, 95% CI 0.34-0.99) compared with non-RA subjects. After the RA incidence date, RA patients were twice as likely to experience unrecognized MIs (hazard ratio [HR] 2.13, 95% CI 1.13-4.03) and sudden deaths (HR 1.94, 95% CI 1.06-3.55) and less likely to undergo coronary artery bypass grafting (HR 0.36, 95% CI 0.16-0.80) compared with non-RA subjects. Adjustment for the CHD risk factors did not substantially change the risk estimates. CONCLUSION: Patients with RA have a significantly higher risk of CHD when compared with non-RA subjects. RA patients are less likely to report symptoms of angina and more likely to experience unrecognized MI and sudden cardiac death. The risk of CHD in RA patients precedes the ACR criteria-based diagnosis of RA, and the risk cannot be explained by an increased incidence of traditional CHD risk factors in RA patients.

Mutations in CHEK2 associated with prostate cancer risk.

The DNA-damage-signaling pathway has been implicated in all human cancers. However, the genetic defects and the mechanisms of this pathway in prostate carcinogenesis remain poorly understood. In this study, we analyzed CHEK2, the upstream regulator of p53 in the DNA-damage-signaling pathway, in several groups of patients with prostate cancer. A total of 28 (4.8%) germline CHEK2 mutations (16 of which were unique) were found among 578 patients. Additional screening for CHEK2 mutations in 149 families with familial prostate cancer revealed 11 mutations (5 unique) in nine families. These mutations included two frameshift and three missense mutations. Importantly, 16 of 18 unique CHEK2 mutations identified in both sporadic and familial cases were not detected among 423 unaffected men, suggesting a pathological effect of CHEK2 mutations in prostate cancer development. Analyses of the two frameshift mutations in Epstein Barr virus-transformed cell lines, using reverse-transcriptase polymerase chain reaction and western blot analysis, revealed abnormal splicing for one mutation and dramatic reduction of CHEK2 protein levels in both cases. Overall, our data suggest that mutations in CHEK2 may contribute to prostate cancer risk and that the DNA-damage-signaling pathway may play an important role in the development of prostate cancer.