eMERGE Network Supplemental Genotyping Project – Phenotype Description & Specifications
Lipids
Phenotype Description:
Version Date
May 18, 2010
Contact
Jennifer A. Pacheco ( japacheco@northwestern.edu
)
Project Title
Genetic variation that predicts serum lipid levels, specifically total cholesterol, HDL
(high density lipoprotein), & LDL (low density lipoprotein).
Phenotype Description &
Outline of Project
Sites Involved / Rough
Estimate of Sample Size
1.
Find all patients that have had a complete lipid panel, which inc. total serum cholesterol, HDL, & LDL
2.
Find the earliest date each patient had any secondary cause of hyperlipidemia or other factor that affects lipid levels, such as statin medication use a.
Antilipemic medication use i.
Prescription order, fill/refill, or medication list ii.
Abrupt change in lipid level that indicates anti-lipid medication use when all fills not available b.
HRT (Hormone Replacement Therapy) or hormonal contraceptive use c.
Diabetes d.
Hypo- or hyper-thyroidism e.
Cancer
3.
Collect all lipid measurements that occur before the exclusions.
At Northwestern, >80% of subjects have a lipid panel with all 3 measures, and
~40% have at least 2 lipid panels that occur before any exclusions. Marshfield reports a similar percentage with eligible lipid panels from their HDL study. Group
Health, Mayo, and Vanderbilt have 80-99% of their patients having lab data, and lipid profiles are a relatively common laboratory. Therefore, we estimate having at least 8,000 already genotyped individuals to study.
Scientific Relevance/
Rationale
Desired variables
(essential for analysis indicated by *)
Limitations/ Potential
Obstacles/
Measurement Issues
Previous GWAS/
Genomic Literature on
Phenotype
A few large GWAS studies for lipid levels have recently been reported. Seven loci for HDL-C, 7 for LDL-C and 9 for triglycerides have been reported previously and three very recent studies reported an additional 20 loci. Despite the large number of loci that have been reported to date, as with other common diseases and traits, these variants account for only a fraction of the heritability, thus leaving most of the heritability yet to be explained and room for additional large studies.
*Basic demographic data: age, gender, race, ethnicity
*Lipid measures, inc. total serum cholesterol, HDL, LDL, and triglycerides, and date(s) collected
*BMI
Earliest dates any exclusions occurred

Detecting those on statins where we don’t have Rx, currently exploring if decrease >20% in LDL &/or total cholesterol accurately identifies patients on statins.

Minimum number of lipid panels to require before exclusions to ensure adequate measures, could require at least 2
 Which lipid panels to use, initially using outpatient median.
 How strict to be w/ exclusions to rule out secondary causes of hyperlipidemia, esp. with regards to our diabetes & hypothyroidism algorithms**.
Reviewed in:
Manolio TA. Cohort studies and the genetics of complex disease. Nature Genetics.
2009; 41(1):5-6.
Last updated: 4/17/2020 Page 1

APPENDIX
Below is a flowchart depicting the lipids phenotyping process. yes yes
Anti-lipid meds?
Genotyped
Cohort yes
Abrupt change in lipid lab value?
At least 2 Lipid panels?
yes
HRT/Oral contraceptives
?
Earliest exclusion date yes Diabetes?
Lipid panels before earliest exclusion?
yes yes
Hypo- or
Hyperthyroidism?
Lipid panels to study yes Cancer?
Last updated: 4/17/2020 Page 2

Phenotype Specifications:
Dates to extract for each exclusion are as follows, with diagnosis codes and medications to use listed at the end of the appendix.
Exclusion dates:

Abrupt change (currently >20% decrease in total cholesterol or LDL) in lipid level: date of first lab that had the abrupt change

Medications: earliest order or prescription date

Diabetes, earliest of the following dates: o from the Northwestern type 2 diabetes algorithm**:
 earliest diagnosis date
 earliest medication order or prescription date for:

insulin, pramlintide (Symlin), or

type 2 diabetes medication
 earliest lab date where abnormal lab value as follows:

random glucose > 200mg/dl,

fasting glucose > 125 mg/dl, or
 hemoglobin A1c ≥ 6.5%. o earliest diagnosis date of any other diabetes diagnosis listed below

Hypo- or Hyper-thyroidism, earliest of the following dates: o from the Vanderbilt hypothyroidism algorithm**:
 earliest hypothyroidism diagnosis date
 earliest hypothyroidism (thyroid replacement) medication prescription date
 earliest abnormal TSH or FT4 lab date o earliest diagnosis date of any other hypo- or hyper-thyroidism diagnosis listed below

Cancer, earliest of the following dates: o earliest diagnosis date from diagnosis codes o earliest diagnosis date from cancer/tumor registry, if one exists
**Currently, we’re not requiring that patients meet all the criteria to be a case for type 2 diabetes or hypothyroidism using Northwestern’s & Vanderbilt’s algorithms, respec tively; we’re just requiring that they have at least one of the critieria listed, as we’re trying to also capture type 1 diabetics and other forms of hypothyroidism that may affect lipid levels
Last updated: 4/17/2020 Page 3

ICD-9 diagnosis codes:
Diabetes:
250* Diabetes Type 1 and 2
357.2 Diabetic Neuropathy
362.01-362.02 Diabetic Retinopathy
583.81 Diabetic Nephropathy
Hypothyroidism:
243* Congenital hypothyroidism
244* acquired hypothyroidism
245 thyroiditis
245.2 chronic lymphocytic thyroiditis
245.8 chronic thyroiditis NEC/NOS
245.9 thyroiditis NOS
Hyperthyroidism:
242.00-242.33
242.90-242.93
Cancer : between 140* and 208*
*any number of digits after the decimal point
Last updated: 4/17/2020 Page 4

Medications:
Antilipemic medications: Statins, Niacins, Fibrates & combinations thereof:

Atorvastatin, Simvastatin, Pravastatin, Lovastatin, Cerivastatin, Rosuvastatin,
Fluvastatin, Pitavastatin

Gemfibrozil/Fibrate, Fenofibrate, Cholestyramine

Niacin/statin combinations

Niacin, inc. generic names: 'INOSITOL/NIACIN','FOLIC
ACID/NIACINAMIDE/CU/ZNOX', 'NIACINAMIDE'
HRT (Hormone Replacement Therapy) or hormonal contraceptives inc.
Estrogen/Androgen , at least oral, implant, patch & other forms that are not creams/topical:

estrogen

ethinyl estradiol, Desogestrel-Ethinyl Estradiol, & other estradiol combinations

Etonogestrel

levonorgestrel

medroxyPROGESTERone

norethindrone

Norgestrel
Optional NLP used by Marshfield in their HDL algorithm to find Estrogen use:
Earliest mention of the following Estrogen/Androgen drug use in clinical notes
(regardless of age or gender) ALORA, CENESTIN, CLIMARA, CLIMARA PRO,
COMBIPATCH, DELESTROGEN, ESTRACE, ESTRADERM, ESTRATAB,
ESTRATEST, ESTRATEST H.S., ESTROGEN, FEMHRT, MENEST, OGEN, ORTHO-
EST, ORTHO-PREFEST, PREMARIN, PREMPHASE, VIVELLE, VIVELLE-DOT
Excluded any records where topical or cream was indicated in the flanking text.
Searched the flanking text in records where the drug name='ESTROGEN' for the following terms: post menopause, post menopause, postmenopausal, on estrogen, went off estrogen, stop estrogen, on unopposed estrogen, estrogen replacement, history of estrogen use, estrogen patch, estrogen usage, estrogen therapy, estrogen pill, unopposed estrogen use, chronic estrogen use.
Kept records where drug name="ESTROGEN" and flanking text contained one of the above terms and there was no indicator of topical or cream in the flanking text.
Type 2 diabetes medications:
Drug class
Sulfonylureas
Brand name Generic name acetohexamide
Sulfonylureas
Sulfonylureas
Sulfonylureas
Sulfonylureas
Diabinese
Glucotrol
Glucotrol XL
Tolazamide chlorpropamide glipizide glipizide
Sulfonylureas
Sulfonylureas
Sulfonylureas
Sulfonylureas
Meglitinides
Meglitinides
Biguanides
Thiazoldinediones
Micronase
Glynase
Diabeta
Amaryl
Prandin
Starlix
Glucophage
Avandia glyburide glyburide glyburide glimepiride repaglinide nateglinide metformin rosiglitazone
Last updated: 4/17/2020 Page 5

Thiazoldinediones
Thiazoldinediones
Alpha-glucosidase inhibitors
Alpha-glucosidase inhibitors
DPPIV inhibitor
Injectables
ACTOS
Precose
Glyset
Januvia
Byetta pioglitazone troglitazone acarbose miglitol sitagliptin exenatide
Hypothyroidism medications (from Vanderbilt hypothyroidism algorithm for cases):
Levothyroxine, synthroid, Levoxyl unithroid, armour thyroid, desiccated thyroid, cytomel, triostat, liothyronine, synthetic triiodothyronine, liotrix, thyrolar, T3
*
and T4
*
Last updated: 4/17/2020 Page 6