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Study Description

The electronic Medical Records and Genomics (eMERGE) Network is a consortium of five participating sites (Group Health Seattle, Marshfield Clinic, Mayo Clinic, Northwestern University, and Vanderbilt University) funded by the NHGRI to investigate the use of electronic medical record systems for genomic research. The goal of eMERGE is to conduct genome-wide association studies in approximately 19,000 individuals using EMR-derived phenotypes and DNA from linked Biorepositories.

Using electronic phenotyping methods, the consortium used DNA samples from all participating sites to explore the genetic determinants of resistant hypertension. Treatment resistant hypertension is a common health problem in the clinical setting. A basic definition of resistant hypertension included subjects with uncontrolled blood pressure despite use of three antihypertensive medications or subjects requiring four or more medications to maintain control. Other conditions, such as secondary causes of hypertension, were exclusions.

Site and participants include:

Vanderbilt University: BioVU, Vanderbilt's DNA databank, is an enabling resource for exploration of the relationships among genetic variation, disease susceptibility, and variable drug responses, and represents a key first step in moving the emerging sciences of genomics and pharmacogenomics from research tools to clinical practice. BioVU acquires DNA from discarded blood samples collected from routine patient care. The biobank is linked to de-identified clinical data extracted from Vanderbilt's EMR, which forms the basis for phenotype definitions used in genotype-phenotype correlations.

Marshfield Clinic: The Marshfield Clinic Personalized Medicine Research Project is a population-based biobank in central Wisconsin with more than 20,000 adult subjects who provided written, informed consent to access their medical records and provided a blood sample from which DNA was extracted and plasma and serum stored. In addition to an average of 30 years of medical history data, a questionnaire about environmental exposures, including a detailed food frequency questionnaire, is available to facilitate gene/environment studies.

Northwestern University: The NUgene Project is a repository with longitudinal medical information from participating patients at affiliated hospitals and outpatient clinics from the Northwestern University Medical Center. Participants' DNA samples are coupled with data from a self-reported questionnaire and continuously updated data from our Electronic Medical Record (EMR) representing actual clinical care events. Northwestern has a state-of-the art, comprehensive inpatient and outpatient EMR system of over 2 million patients. NUgene has broad access to participant data for all outpatient visits as well as inpatient data via a consolidated data warehouse. NUgene participants consent to distribution and use of their coded DNA samples and data for a broad range of genetic research by third-party investigators.

Group Health(GH)/University of Washington (UW): Aging and Dementia eMERGE study biorepository leverages rich population-based longitudinal data from both electronic medical records and in-depth research data to explore genome wide associations. Participants include Seattle-area members of GH (a large integrated health care system in Washington State) consented and enrolled in 1) the UW Alzheimer's Disease Patient Registry (ADPR) and 2) the Adult Changes in Thought (ACT) study. The ADPR (PI: Eric B. Larson; NIH/NIA U01 AG 006781) is a population-based registry of incident dementia cases designed to identify all new Alzheimer's Disease cases within GH from 1987 to 1996. Medical history, physical, laboratory testing, and neuropsychological testing were performed on all consenting potential cases for determination of dementia status by a consensus conference. The study base of the ADPR population was stable with an attrition rate of less than 1%/year. The ACT study (PI: Eric B. Larson; NIH/NIA U01 AG 006781) is an ongoing community-based cohort study of aging and dementia. The original cohort of 2,581 randomly selected dementia-free members age 65 and older was enrolled in 1994-1996 and expanded by 811 in 2000-2002. Continuous enrollment to maintain a cohort of 2,000 dementia free persons began in 2005. Participants receive biennial assessment including cognitive status determination. The ACT sub-sample is stable; for the original cohort, median enrollment in GH was 19 years prior to joining the ACT study, and 85% of the cohort has ≥ 10 years of GH enrollment. DNA for the ADPR participants were obtained through a companion study, Genetic Differences in Cases and Controls (PI: Walter Kukull; NIH/NIA R01 AG007584). DNA obtained through both studies were extracted from blood using Gentra Systems Puregene methods. DNA concentration is determined by UV optical density. All samples are checked for quality by 260/280 ratio. For long-term storage, samples are aliquoted and stored at -70°C.

Mayo Clinic: The Mayo biobank is a disease-specific biobank for vascular diseases including peripheral arterial disease (PAD). PAD patients were identified from individuals referred to the non-invasive vascular laboratory for lower extremity arterial evaluation. Since 1997, laboratory findings have been recorded into an electronic database employing an in-house software package for data archiving and retrieval; this data becomes part of the Mayo EMR. Patients referred to the center with suspected PAD undergo a comprehensive non-invasive evaluation including the ankle-brachial index (ABI) - the ratio of blood pressure measured in the upper arms divided by blood pressure measured at the ankles. Controls subjects are identified from patients referred to the Cardiovascular Health Clinic for stress ECG. The prevalence of PAD in patients with normal exercise capacity who do not have inducible ischemia on the stress ECG, was <1%. Data regarding risk factors for atherosclerosis such as diabetes, dyslipidemia, hypertension, and smoking are ascertained from the EMR.

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Publicly Available Data (Public ftp)

Connect to the public download site. The site contains release notes and manifests. If available, the site also contains data dictionaries, variable summaries, documents, and truncated analyses.

Study Inclusion/Exclusion Criteria

Subjects were determined using electronic algorithms deployed with an existing EMR.

CASE DEFINITION:
Subject has ≥ 4 meds simultaneous* med classes below mentioned on at least 2 occasions ≥ 1 month apart (does not have to be the same med classes in each of the 2 occasions);
OR
Subject has two outpatient (if possible) measurements of SBP > 140 or DBP > 90 at least one month after meeting medication criteria while still on 3 simultaneous med classes
AND
has 3 simultaneous* med classes below (and does not meet Case Type 1) mentioned on at least 2 occasions ≥ 1 month apart (does not have to be the same med classes in each of the 2 occasions).

*Simultaneous is defined as evidence that they are taking the medications concurrently. Such evidence could be presence of the medications in the same medication list (e.g., problem list, clinic note, or discharge summary) or via medication refill data. If using the latter method, the algorithm should find evidence of at least repeated overlapping scripts for each drug if you are using this method.

S: start
R:refill
X-axis: is time
BP: 150/80-----------145/80---154/74
Drug 1 : S----->R1------>R2---->R3---->R4
Drug 2: -----S------>absent
Drug 3:----------S------>R1---->R2---->R3--
Drug 4:-------------------S---->R1----->R2----
At R1 of Drug 4, patient qualifies for Case Type 2

Note: For those using NLP to define medications, we require a dose, strength, route, or frequency present with the medication name to insure that the medication represents a prescribed medication.

From the above, subjects with any of the following codes appearing in the record at any time were excluded:

ICD9 codesDescription
194.0MALIGN NEOPL ADRENAL
227.0BENIGN NEOPLASM ADRENAL
255.0, 255.1, 255.2, 255.3, 255.6, 255.8, 255.9Disorders of adrenal glands (excludes adrenal insufficiencies - 255.4 and 255.5)
405.*SECONDARY HYPERTENSION
416.*Chronic pulmonary heart disease
581.*Nephrotic syndrome
582.*Chronic glumerulonephritis
745.*Bulbus cordis anomalies
747.1*COARCTATION OF AORTA

From the cases above, all subjects with the following codes were excluded only if the resistant hypertension only exists within five years before or after one of the codes below. For example, this means that one could ignore medications mentioned during a 5-year time frame before or after the below codes.

ICD9 codesDescription
242.*Thyrotoxicosis
246Disorder of thyrocalcitonin secretion
246.8DISORDERS OF THYROID NEC
246.9DISORDER OF THYROID NOS
252.8PARATHYROID DISORDER NEC
252.9PARATHYROID DISORDER NOS
320.2ORGANIC SLEEP APNEA
327.21PRIMARY CENTRAL SLEEP APNEA
327.23OBSTRUCTIVE SLEEP APNEA
327.27CEN SLEEP APNEA IN COND CLASS
327.29OTHER ORGANIC SLEEP APNEA
599.6*OBSTRUCTIVE UROPATHY

From the cases above, exclude the subject if GFR < 30 ml/min before the time of meeting the CASE 1 or 2 definitions or within 6 months after meeting the medication definition.

GFR should be calculated using the Modification of Diet in Renal Disease (MDRD) formula:
eGFR = 186 x Serum Creatinine-1.154 x Age-0.203 x [1.210 if Black] x [0.742 if Female]
(source: http://en.wikipedia.org/wiki/Renal_function#Estimated_GFR_.28eGFR.29_using_Modification_of_Diet_in_Renal_Disease_.28MDRD.29_formula)

Exclude all patients with an Ejection Fraction (EF or LVEF) <35% within 1 year before or after meeting the CASE 1 definition.

CONTROL DEFINITION:

Controls - Case 1: Subjects with controlled hypertension
Has outpatient (if possible) measurement of SBP > 140 or DBP > 90 prior to meeting medication criteria OR ICD9 401.* code at any time
AND
has 1 med from med classes below (and never has more than 1 simultaneous med class, although the med class can change)
AND
Has all SBP < 135 and DBP < 90 one month AFTER BP meds (require at least 1 BP measurement)

Controls - Case 2: Subjects without evidence of hypertension
Has no outpatient (if possible) measurement of SBP > 140 or DBP > 90
AND
No mention of any anti-hypertensive from med classes below at any time
AND
Does not have any hypertension ICD9 code: (401, 401.0, 401.9, 402.*, 403.* 404.*)

For all controls: Exclude all patients with EF < 35% or with the following ICD9 codes:

ICD9 codesDescription
194.0MALIGN NEOPL ADRENAL
227.0BENIGN NEOPLASM ADRENAL
255.0, 255.1, 255.2, 255.3, 255.6, 255.8, 255.9Disorders of adrenal glands (excludes adrenal insufficiencies - 255.4 and 255.5)
405.*SECONDARY HYPERTENSION
416.*Chronic pulmonary heart disease
581.*Nephrotic syndrome
582.*Chronic glumerulonephritis
745.*Bulbus cordis anomalies
747.1*COARCTATION OF AORTA

Subjects with the following codes are allowable as controls (no matter when they occurred):

ICD9 codesDescription
242.*Thyrotoxicosis
246Disorder of thyrocalcitonin secretion
246.8DISORDERS OF THYROID NEC
246.9DISORDER OF THYROID NOS
252.8PARATHYROID DISORDER NEC
252.9PARATHYROID DISORDER NOS
320.2ORGANIC SLEEP APNEA
327.21PRIMARY CENTRAL SLEEP APNEA
327.23OBSTRUCTIVE SLEEP APNEA
327.27CEN SLEEP APNEA IN COND CLASS
327.29OTHER ORGANIC SLEEP APNEA
599.6*OBSTRUCTIVE UROPATHY

Medication Classes:

Hydralazine: Hydralazine (Apresazide, bidil, apressoline)

Minoxidil: (Loniten)

Renin antagonist: aliskiren (Tekturna)

Central alpha agonists: clonidine (catapres) (catapress); guanabenz; methyldopa; methyldopate

ACEI/ARB: candesartan (Atacand); Irbesartan (avapro); lisinopril (prinivil, zestril); trandolapril (Mavik, gopten, odrik); Losartan (cozaar); enalapril (enalaprilat); valsartan (diovan); telmisartan (Micardis); moexipril; quinapril (accupril); ramipril (altace); fosinopril (monopril); eprosartan; olmesartan (benicar); perindopril (Aceon); captopril (Capoten); benazepril (lotensin);

Aldosterone antagonists: spironolactone (Aldactone); eplerenone (inspra)

Diuretics (count each instance as part of the same class, even if on more than one concurrently): Thiazide: hydrochlorothiazide (Esidrix); indapamide (lozol, natrilix); cyclothiazide; chlorothiazide; chlorthalidone; bendroflumethiazide; benzothiazide; K-sparing diuretics: amiloride (midamor); triamterene (Dyrenium); Loop diuretics: furosemide (lasix), torsemide (demadex), ethacrynic acid (ethacrynate, edecrin); bumetanide (bumex)

Note: the Diuretic combination meds now count as a single class: Dyazide, Moduretic, Maxzide

Alpha antagonists: prazosin (minipress); doxazosin (cardura)

Non-dihydro CCBs: verapamil (calan, covera, isoptin, verelan); diltiazem (dilt, tiazac, cardizem)

Dihydro CCBs: isradipine (Dynacirc); nicardipine; nifedipine (procardia); nisoldipine; felodipine (plendil); Amlodipine (norvasc, caduet); bepridil (vascor)

Beta Blockers: propranolol (inderal); metoprolol (toprol); labetalol (trandate); nadolol (corgard); esmolol (brevibloc); pindolol; penbutolol (levatol); Labetalol (Normodyne); atenolol (tenormin); carvedilol (coreg); bisoprolol (Zebeta);

*Thiazide/BB: corzide , Tenoretic, lopressor HCT

*Thiazide/ACEI_ARB: zestoretic, Avalide, hyzaar, uniretic, benicar HCT, accuretic, Teveten HCT, lotensin HCT; micardis HCT; atacand HCT; Diovan HCT; Monopril HCT

*Thiazide/aldosterone antagonist: aldactazide

*Thiazide/Renin antagonist: Tekturna HCT

*A match of a combination medication counts as two med classes. We have not included the generics for combination medications to avoid possible double counting of the medication classes during a search.

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Whole Genome Genotyping Illumina Human660W-Quad_v1_A 592839 1048965
Whole Genome Genotyping Illumina Human1M-Duov3_B 1185051 1049348
Selected publications
Diseases/Traits Related to Study (MESH terms)
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Study Attribution