Lipids Phenotype Description



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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

  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

    1. Antilipemic medication use

      1. Prescription order, fill/refill, or medication list

      2. Abrupt change in lipid level that indicates anti-lipid medication use when all fills not available

    2. HRT (Hormone Replacement Therapy) or hormonal contraceptive use

    3. Diabetes

    4. Hypo- or hyper-thyroidism

    5. Cancer

  3. Collect all lipid measurements that occur before the exclusions.

Sites Involved / Rough Estimate of Sample Size

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

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.

Desired variables (essential for analysis indicated by *)

*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

Limitations/ Potential Obstacles/ Measurement Issues

  • 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**.

Previous GWAS/ Genomic Literature on Phenotype

Reviewed in:

Manolio TA. Cohort studies and the genetics of complex disease. Nature Genetics. 2009; 41(1):5-6.




APPENDIX
Below is a flowchart depicting the lipids phenotyping process.


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:

    • 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%.

    • earliest diagnosis date of any other diabetes diagnosis listed below




  • Hypo- or Hyper-thyroidism, earliest of the following dates:

    • from the Vanderbilt hypothyroidism algorithm**:

      • earliest hypothyroidism diagnosis date

      • earliest hypothyroidism (thyroid replacement) medication prescription date

      • earliest abnormal TSH or FT4 lab date

    • earliest diagnosis date of any other hypo- or hyper-thyroidism diagnosis listed below




  • Cancer, earliest of the following dates:



**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, respectively; 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

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

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

Brand name

Generic name

Sulfonylureas




acetohexamide

Sulfonylureas




Tolazamide

Sulfonylureas

Diabinese

chlorpropamide

Sulfonylureas

Glucotrol

glipizide

Sulfonylureas

Glucotrol XL

glipizide

Sulfonylureas

Micronase

glyburide

Sulfonylureas

Glynase

glyburide

Sulfonylureas

Diabeta

glyburide

Sulfonylureas

Amaryl

glimepiride

Meglitinides

Prandin

repaglinide

Meglitinides

Starlix

nateglinide

Biguanides

Glucophage

metformin

Thiazoldinediones

Avandia

rosiglitazone

Thiazoldinediones

ACTOS

pioglitazone

Thiazoldinediones




troglitazone 

Alpha-glucosidase inhibitors

Precose

acarbose

Alpha-glucosidase inhibitors

Glyset

miglitol

DPPIV inhibitor

Januvia

sitagliptin

Injectables

Byetta

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*




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