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Lecture Series

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Peer-Reviewed Clinical Literature

True Health strives to ensure that the biomarkers we offer are clinically valuable and based in evidence. View the supporting research for our testing below.

Traditional Lipids

  1. Sachdeva A, Cannon CP, Deedwania PC, et al. Lipid levels in patients hospitalized with coronary artery disease: An analysis of 136,905 hospitalizations in Get With The Guidelines. Am Heart J. 2009; 157(1):111-117.e2.

    Among patients hospitalized with coronary artery disease, almost 50% have low-density lipoprotein-cholesterol (LDL-C) levels <100 mg/dL. The findings of this large analysis of US patients suggests that LDL-C alone is insufficient to determine cardiovascular risk.

Lipoproteins and Additional Lipids

  1. Sniderman AD, Islam S, Yusuf S, McQueen MJ. Discordance analysis of Apolipoprotein B and non-high density lipoprotein cholesterol as markers of cardiovascular risk in the INTERHEART study. Atherosclerosis. 2012; 225(2):444-449.

    This study tests within the INTERHEART database (9,345 cases and 12,120 controls from 52 countries) whether apoB or non-HDL-C are equivalent markers of risk when they are discordant. Conclusion: Discordance analysis demonstrates that apoB is a more accurate marker of cardiovascular risk than non–HDL-C.

  2. De Graaf J, Couture P, Sniderman AD. A diagnostic algorithm for the atherogenic apolipoprotein B dyslipoproteinemias. Nat Clin Prac Endocrinol Metab. 2008; 4:608-618.

    This article presents a diagnostic algorithm for lipid disorders that is based on concentrations of total cholesterol, triglyceride, and apoB. By including apoB values, lipoprotein number and composition can be deduced and each of the classic dyslipoproteinemias identified. This algorithm can help physicians to improve the diagnosis and treatment of dyslipoproteinemias.

  3. Sniderman AD. Differential response of cholesterol and particle measures of atherogenic lipoproteins to LDL-lowering therapy: implications for clinical practice. J Clin Lipidol. 2008; 2(1):36-42.

    Many patients who achieve LDL-C and non–HDL-C target levels do not achieve correspondingly low, population-equivalent ApoB or LDL-P targets. Relying on the measurement of LDL-C and non–HDL-C can create a treatment gap in which the opportunity to provide the greatest LDL-lowering therapy is lost. “At least 6 discordance analyses have now been published, and all show how apoB is superior to either LDL-C or non–HDL-C as a marker of cardiovascular risk. If evidence actually matters, that should settle it. NMR gives the equivalent information as apoB. So, I regard NMR as an equivalent acceptable technique to measure LDL.”

  4. Thanassoulis G, Williams K, Ye K, et al. Relations of change in plasma levels of LDL-C, non-HDL-C and apoB with risk reduction from statin therapy: A meta-analysis of randomized trials. J Am Heart Assoc. 2014; 3(2):e000759.

    This meta-analysis of 7 major placebo-controlled statin trials demonstrated that the relative risk reduction from statin therapy was more closely related to reductions in apoB than in either non-HDL-C or LDL-C.

  5. Brown VW, Sacks FM, Sniderman AD. JCL roundtable: Apolipoproteins as a causative elements in vascular disease. J Clin Lipidol. 2015; 9:733-740.

    Cholesterol measures are variable and may not reveal all the valuable information that can be used to treat patients. The amount of cholesterol in each lipoprotein particle varies greatly between patients. Therefore, patients with a low-density lipoprotein cholesterol level considered optimal by current guidelines, may have abnormally high or low numbers of particles containing apolipoprotein B (apoB).

  6. Wilkins JT, Li RC, Sniderman A. Discordance between apolipoprotein B and LDL-cholesterol in young adults predicts coronary artery calcification The CARDIA Study. J Am Coll Cardiol. 2016; 67:193–201.

    “There is a dose-response association between apoB in young adults and the presence of midlife coronary atherosclerosis, independent of baseline traditional CVD risk factors. High apoB and low LDL-C or non–HDL-C discordance was also associated with year 25 coronary artery calcium score, in adjusted models.

  7. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm-2016 executive summary. Endocr Prac. 2016; 22(1):84-113.

    The 2016 AACE/ACE guidelines now incorporate not only apoB, but also LDL-P into the lipid treatment section of its diabetes management consensus statement.

  8. Rosenson R, Hegele RA, Gotto AM. Integrated measure for atherogenic lipoproteins in the modern era: risk assessment based on apolipoprotein B. J Am Coll Cardiol. 2016; 67:193–201.

    Three world-class lipidologists make the case that it is time to recognize that several lines of evidence now argue against the continued use of LDL-C as a first-line measure of lipid-related risk. They note that on the basis of differences in CVD events at 10 years, a treatment strategy that used non–HDL-C would potentially prevent 300,000 more events than would an LDL-C strategy, and an apoB strategy 500,000 more than would a non–HDL-C strategy. Although some consensus statements argue that new prospectively designed clinical trials must be performed to validate a biomarker, conducting trials using therapies already proven to reduce CVD events is neither ethical nor practical. The authors of this article also note that several professional societies have proposed measuring apoB or LDL particle concentration as an additional measure for risk assessment after consideration
    of LDL-C and non–HDL-C.

  9. Cromwell WC, Otvos JD, Keyes MJ. LDL particle number and risk of future cardiovascular disease in the Framingham Offspring Study—Implications for LDL management. J Clin Lipidol. 2007; 1(6):583–592.

    In a large community-based sample, LDL-P was a more sensitive indicator of low CVD risk than either LDL-C or non–HDL-C, suggesting a potential clinical role for LDL-P as a goal of LDL management.

  10. Otvos JD, Mora S, Shalaurova I, et al. Clinical implications of discordance between low-density lipoprotein cholesterol and particle number. J Clin Lipidol. 2011; 5(2):105–113.

    For individuals with discordant LDL-C and LDL-P levels, the LDL-attributable atherosclerotic risk is better indicated by LDL-P.

  11. Degoma EM, Davis MD, Dunbar RL, et al. Discordance between non-HDL-cholesterol and LDL-particle measurements: Results from the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis. 2013; 229(2):517-523.

    The results of this study demonstrated that disagreement between LDL-P and non-HDL-C was common and were significantly associated with several clinical characteristics. In the setting of discordance, LDL-P was more closely associated with carotid intima media thickness (CIMT) and carotid artery calcium (CAC) than was non-HDL-C.

  12. Garvey WT, Kwon S, Zheng D, et al Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance. Diabetes. 2003; 52(2):453-462.

    The authors of this study concluded the following: 1) Insulin resistance had profound effects on lipoprotein size and subclass particle concentrations for VLDL, LDL, and HDL when measured by NMR; 2) In type 2 diabetes, the lipoprotein subclass alterations were moderately exacerbated but could be primarily attributed to the underlying insulin resistance; and 3) Insulin resistance–induced changes in the NMR lipoprotein subclass profile predictably increased the risk of cardiovascular disease.

  13. Toth PT, Grabner M, Punekar RS, et al. Cardiovascular risk in patients achieving low-density lipoprotein cholesterol (LDL-C) and particle (LDL-P) targets. Atherosclerosis. 2014; 235:585-591.

    Among commercially insured patients, higher LDL-P levels were associated with increased CHD risk. High-risk patients who achieved LDL-P <1000 nmol/L received more aggressive lipid-lowering therapy than patients who achieved LDL-C <100 mg/dL; these differences in lipids and therapeutic management were associated with a reduction in CHD/stroke events over 12, 24, and 36 months follow-up.

  14.  Malave H, Castro M, Burkle J, et al. Evaluation of Low-Density Lipoprotein Particle Number Distribution in Patients With Type 2 Diabetes Mellitus With Low-Density Lipoprotein Cholesterol < 50 mg/dL and Non-High-Density Lipoprotein Cholesterol < 80 mg/dL. Am J Cardiol. 2012; 110(5):660-665.

    Despite attaining LDL cholesterol <50 mg/dL or non-HDL cholesterol <80 mg/dL, patients with diabetes had significant variation in LDL particle levels, with most having LDL particle concentrations >500 nmol/L, suggesting residual risk for coronary heart disease.

  15. Buff-Prado K, Shugg S, Backstrand JR. Low-density lipoprotein particle number predicts coronary artery calcification in asymptomatic adults at intermediate risk of cardiovascular disease. J Clin Lipidol. 2011; 5(5):408–413.

    Total LDL particle number (LDL-P) was more strongly associated with coronary artery calcium (CAC) than were traditional lipoprotein measures. Patients in the highest tertile of total LDL-P (1935–3560 nmol/L) were 3.7 times more likely to exhibit CAC than those in the lowest tertile (620–1530 nmol/L). Small LDL-P was an independent predictor of CAC, an effect that remained significant after adjustment for LDL-C, HDL-C, triglycerides, and non–HDL-C.

  16. Mackey RH, Greenland P, Goff DC, et al. High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol. 2012; 60(6):508–516.

    Very important study showing HDL-C had little meaning once adjusted for total HDL-P: Adjusting for each other and LDL-P substantially attenuated associations of HDL-C, but not HDL-P, with cIMT (carotid intimal thickening) and CHD. Potential confounding by related lipids or lipoproteins should be carefully considered when evaluating HDL related risk.

  17. Zaid M, Fujiyoshi A, Miura K,  High-density lipoprotein particle concentration and subclinical atherosclerosis of the carotid arteries in Japanese men.  Atherosclerosis. 2015; 239(2):444-450.

    Compared to HDL-C, HDL-P is more strongly associated with measures of carotid atherosclerosis, in a cross-sectional study of Japanese men. These findings demonstrate that HDL-P is a strong correlate of subclinical atherosclerosis, even in a population at low risk for CHD.

  18. Bays HE, Jones PH, Brown WV, Jacobson TA.  National Lipid Association annual summary of clinical lipidology 2015. J Clin Lipidol. 2014; 8:S1-S36.

    Because the cholesterol content of LDL particles is variable, there may be discordance between the cholesterol carried by LDL particles and the number of LDL particles. When discordant, ASCVD risk often tracks better with LDL-P than with LDL-C.  Residual ASCVD risk may be better predicted by on-treatment LDL-P levels than by LDL-C levels. Given that statin therapy reduces non–HDL-C and LDL-C to a greater extent than LDL-P, LDL-P may better assess on-treatment residual risk than does measurement of non–HDL-C or LDL-C. Thus, residual increases in LDL-P may prompt more aggressive lipid-altering therapy.

  19. Pencina MJ, D’Agostino RB, Zdrojewski T, et al. Apolipoprotein B improves risk assessment of future coronary heart disease in the Framingham Heart Study beyond LDL-C and non-HDL-C. Eur J Prev Cardiol. 2015; 22(10):1321-1327.

    ApoB measurement improves risk assessment of future coronary heart disease events above and beyond LDL-C or non-HDL-C, a finding that is consistent with coronary risk being more closely related to the number of atherogenic apoB particles than to the mass of cholesterol within them.

  20. Tehrani DM, Zhao Y, Blaha MJ, Mora S, Mackey RH, et al. LDL discordance and higher LDL-P in MetS, and higher LDL-C and lower HDL-P in DM, predict CHD and CVD, supporting a potential role for examining lipoprotein particles and discordances in those with MetS and DM. Am J Cardiol. 2016; 117:1921-1927.

    LDL discordance and higher LDL-P in Metabolic Syndrome, and higher LDL-C and lower HDL-P in DM, predict CHD and CVD, supporting a potential role for examining lipoprotein particles and discordances in those with Metabolic Syndrome and DM.

  21. Kronenberg F, Utermann G. Lipoprotein(a): resurrected by genetics. J Intern Med. 2013; 273(1);6–30.

    Excellent current review: Lp(a) concentration is relatively independent of age and gender. Lp(a) is currently considered to be the strongest genetic risk factor for coronary heart disease (CHD).

  22. McConnell JP, Guadagno PA, Dayspring TD, et al. Lipoprotein(a) mass: a massively misunderstood metric. J Clin Lipidol. 2014; 8:550-553.

    At the time of this study, there were no commercially available assays that were completely insensitive to the variability in Lp(a) particle mass, which arises not only from differences in apo(a) isoform mass, but also from variations in lipid mass. Because lipoprotein ‘‘particle number’’ (molar concentration) is superior to component-based metrics (ie, LDL-P vs LDL-C concentrations) for CV disease risk prediction, the authors proposed that the development of a mass-insensitive Lp(a) assay like Lp(a)-P should be a high priority.

  23. Guadagno PA, Summers-Bellin EG, Harris WS, et al. Validation of a lipoprotein(a) particle concentration assay by quantitative lipoprotein immunofixation electrophoresis. Clinica Chimica Acta. 2015; 439:219–224.

    Lipoprotein immunofixation electrophoresis (Lipo-IFE) is a technique that uses electrophoretic separation and apolipoprotein B staining of lipoproteins. Lipo-IFE serum measurement of Lp(a)-P compared well with the mass-based Lp(a) assay (r = 0.95), but was not affected by variations in apo(a) isoform size [a major weakness of Lp(a) assays].

  24. Dayspring TD, Varvel AV, Ghaedi L, et al. Biomarkers of cholesterol homeostasis in a clinical laboratory database sample comprising 667,718 patients. J Clin Lipidol. 2015; 9:807-816.

    In this study, the largest study of its kind, the authors described sample distributions of noncholesterol sterol/stanol biomarkers (markers of cholesterol absorption and synthesis) and characterized their relationship to age, sex, and APOE genotype.

  25. Del Gobbo LC, Imamura F, Aslibekyan S et al. ω-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease Pooling Project of 19 Cohort Studies. JAMA. 2016 Jun 27 [Epub ahead of print]. doi:10.1001/jamainternmed.2016.2925.

    Pooled analysis of 19 studies from 16 countries and over 45,000 individuals demonstrated that biomarker concentrations of seafood and plant-derived ω-3 fatty acids are associated with a modestly lower incidence of fatal coronary heart disease.

  26. Pottala JV, Garg S, Cohen BE, et al. Blood eicosapentaenoic and docosahexaenoic acids predict all-cause mortality in patients with stable coronary heart disease: The Heart and Soul Study. Circ Cardiovasc Qual Outcomes. 2010; 3(4):406-412.

    In patients with stable coronary heart disease, blood n-3 FA levels were inversely associated with total mortality, independent of standard and emerging risk factors, suggesting that reduced tissue n-3 FA levels may adversely affect metabolism.

  27. Harris WS. The Omega-3 Index: Clinical utility for therapeutic intervention. Curr Cardiol Rep. 2010; 12(6):503-508.

    In this review of the clinical utility of a metric, the author concludes that the Omega-3 Index provides optimal health benefits at 8% or higher and appears to fulfill many of the requirements for both a risk marker and a risk factor.

  28. Mozaffarian D, Wu JH. Omega-3 Fatty Acids and Cardiovascular Disease Effects on Risk Factors, Molecular Pathways, and Clinical Events. J Am Coll Cardiol. 2011; 58(20):2047-2067.

    This review focused upon evidence for the cardiovascular effects of n-3 polyunsaturated fatty acids (PUFA) consumption. Current data provide strong evidence that n-3 PUFA are bioactive compounds that can reduce risk of cardiac death.

  29. Kromhout D, de Goede J. Update on cardiometabolic health effects of n-3 fatty acids. Curr Op Lipidol. 2014; 25(1):85–90.

    This review of meta-analyses and prospective cohort studies concluded that there is strong evidence for a protective effect of ω-3 FA on fatal coronary heart disease and for certain atherosclerosis and thrombosis markers.

  30. Heydari B, Abdullah S, Pottala J, et al. Effect of omega-3 acid ethyl esters on left ventricular remodeling after acute myocardial infarction.  Circulation. 2016; 134:378-391.

    In this study, a placebo-controlled trial of participants who presented with an acute myocardial infarction, high-dose omega-3 fatty acids were shown to be beneficial to heart function. This was a Harvard trial, but the HS Omega-3 Index® testing was conducted at True Health Diagnostics. The authors note: “The greatest impact of O-3FA treatment was on RBC EPA and HS Omega-3 Index®, which were increased by 256% and 81%, respectively”.  They concluded: “the study demonstrated a beneficial effect for high-dose O-3FA treatment on adverse LV remodeling after acute MI in patients receiving modern, guidelines-based therapies”.

Inflammation/Myocardial Stress

  1. Everett BM, Ridker PM, Cook NR, Pradhan AD. Usefulness of B-type natriuretic peptides to predict cardiovascular events in women (from the Women’s Health Study). Am J Cardiol. 2015; 116(4):532-537.

    In this prospective study of initially healthy women from the Women’s Health Study, N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations showed statistically significant association with incident cardiovascular disease, independent of traditional cardiovascular risk factors.

  2. Ho JE, Liu C, Lyass A, et al. Galectin-3, a marker of cardiac fibrosis, predicts incident heart failure in the community. J Am Coll Cardiol. 2012; 60(14):1249-56.

    Among 3,353 participants in the Framingham Offspring study, higher concentrations of Galectin-3, a marker of cardiac fibrosis, were associated with increased risk for incident HF and mortality.

  3. Maiolino G, Rossitto G, Pedon L, et al. Galectin-3 predicts long-term cardiovascular death in high-risk patients with coronary artery disease. Arterioscler Thromb Vasc Biol. 2015; 35(3):725-732.

    In patients with high cardiovascular risk who were referred for coronary angiography, galectin-3 is a strong independent predictor of cardiovascular death over a follow-up period of 7.2 years.

  4. Davidson MH, Ballantyne CM, Jacobson TA, et al. Clinical utility of inflammatory markers and advanced lipoprotein testing: Advice from an expert panel of lipid specialists. J Clin Lipidol. 2011; 5(5):338–367.

    This panel of experts concluded the following for C-reactive protein (CRP) on-treatment management decisions: 1) CRP measurement is reasonable and can help guide intensity of therapy for patients with intermediate risk, coronary heart disease (CHD; or a CHD risk equivalent), or a history of recurrent coronary events. 2) CRP measurement can be considered for selected patients among those with family history of premature CHD; however, the clinical utility of CRP in guiding therapy in this setting is less certain and requires further investigation.

  5. Bays HE, Jones PH, Brown WV, Jacobson TA. National Lipid Association annual summary of clinical lipidology 2015. J Clin Lipidol. 2014; 8:S1-S36.

    The inflammatory marker C-reactive protein (CRP) is associated with increased risk of atherosclerotic cardiovascular disease (ASCVD) risk. Lipid-lowering intervention that lowers CRP levels may also reduce ASCVD risk; however, it is unclear whether the reduction in ASCVD risk is due to improved lipid levels or to reduction in CRP alone. Atherosclerosis is an inflammatory process; thus, in selected patients at higher ASCVD risk, clinicians may find measurement of CRP useful to determine the effectiveness of lipid-altering intervention.

  6. Davidson MH, Corson MA, Alberts MJ, et al. Consensus panel recommendation for incorporating lipoprotein-associated phospholipase A2 testing into cardiovascular disease risk assessment guidelines. Am J Cardiology. 2008; 101(12A):51F-57F.

    Due to failure of drugs (e.g. darapladib in two major trials) that significantly reduce Lp-PLA2 activity and concentrations failing to reduce clinical events, Lp-PLA2 is now considered a risk factor but not to be used as an efficacy judge on lipid-modulating drugs. Lp-PLA2 is an indicator that the immune system is trying to attack inflammation. It is no longer considered to be specific for atherosclerosis or plaque as can be seen in other inflammatory states (hepatic, pulmonary, etc).

  7. Meinitzer A, Kielstein JT, Pilz S, et al. Symmetrical and Asymmetrical Dimethylarginine as Predictors for Mortality in Patients Referred for Coronary Angiography: The Ludwigshafen Risk and Cardiovascular Health Study. Clin Chem. 2011;57(1):112-121.

    In 3,229 patients who were undergoing coronary angiography at baseline, serum concentrations of symmetrical dimethylarginine (SDMA) were associated with increased risk for cardiovascular and all-cause mortality.

  8. Szczeklik W, Stodółkiewicz E, Rzeszutko M, et al. Urinary 11-Dehydro-Thromboxane B2 as a predictor of acute myocardial infarction outcomes: results of Leukotrienes and Thromboxane In Myocardial Infarction (LTIMI) study. J Am Heart Assoc. 2016; 5(8):pii: e003702. doi: 10.1161/JAHA.116.003702.

    In the Leukotrienes and Thromboxane In Myocardial Infarction (LTIMI) study of 180 consecutive patients with acute myocardial infarction, 11-dehydro-thromboxane B2 was an independent predictor of 1-year cumulative major adverse cardiovascular events and was negatively correlated with left ventricular ejection fraction on admission.

  9. Pastori D, Pignatelli P, Farcomeni A, et al. Urinary 11-dehydro-thromboxane B2 is associated with cardiovascular events and mortality in patients with atrial fibrillation. Am Heart J. 2015; 170(3):490-7.

    Increasing levels of urinary 11-dehydrothromboxane B2 levels were associated with increasing risk for cardiovascular events in a prospective single-center cohort study of 837 patients with atrial fibrillation.

Genetics

  1. Reitsma PH, Versteeg HH, Middeldorp S. Mechanistic view of risk factors for venous thromboembolism. Arterioscler Thromb Vasc Biol. 2012; 32(3):563-568.

    Prothrombin G and Factor V Leiden are two well-characterized genetic risk factors for venous thromboembolism. In Caucasians, the prevalence of these risk factors varies from 3% to 15%, depending on the geographical location; in other races, these risk factors are extremely rare. The increase in thrombotic risk is about 2- to 3-fold for prothrombin G20210 and 3- to 5-fold for factor V Leiden.

  2. Harris WS, Pottala JV, Thiselton DL, Varvel SA, et al. Does APOE genotype modify the relations between serum lipid and erythrocyte omega-3 fatty acid level? J Cardiovasc Trans Res. 2014; 7(5):526-32.

    This study shows that fish oil supplementation, and thus the Omega-3 Index, is not associated with any deleterious effect on LDL-C, apoB, or LDL particle number. Data were derived from a study of US patients who received services as part of routine clinical care from a predecessor in interest of True Health Diagnostics.

  3. Eichner JE, Dunn ST, Perveen G, Thompson DM, Stewart KE, Stroehla BC. Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol. 2002; 155(6):487-95.

    Review: This article evaluates the evidence for an association between apolipoprotein E gene polymorphisms and cholesterol regulation and cardiovascular disease.

  4. Sobczyńska-Malefora A, Cutler J, Rahman Y. Elevated homocysteine with pseudo-homozygosity for MTHFR677T as predisposing factors for transient ischemic attacks: a case report. Metab Brain Dis. 2016 Jul18 [epub ahead of print] DOI: 10.1007/s11011-016-9875-1.

    This case study discusses the MTHFR C677T polymorphism as the potential cause of hyperhomocysteinemia and neurological events in a young man.

  5. Selhub J. The many facets of hyperhomocystememia: studies from the Framingham cohorts. J Nutr. 2006; 136: 1726s-1730s.

    A thorough evaluation of the relationships between total homocysteine (tHcy) and cardiovascular disease, in the setting of the Framingham Heart Study. The prevalence of stenosis increased with increasing quartiles of tHcy; an association that was more striking in men. The highest levels of homocysteine were associated with greater risk for stroke and cardiovascular and all-cause mortality. Hyperhomocysteinemia was also associated with increased risk for other conditions, such as dementia, hip fracture, and congestive heart failure in adults without prior myocardial infarction.

  6. Botero P, Ormsby WD, Ashrani AA, et al. Do incident and recurrent venous thromboembolism risks truly differ between heterozygous and homozygous factor V Leiden carriers? A retrospective cohort study. Eur J Intern Med. 2016; 30:77-81.
  7. American College of Medical Genetics Consensus Statement on Factor V Leiden Mutation Testing. Available at: http://www.acmg.net/StaticContent/StaticPages/Factor_V.pdf Accessed Aug 23 2016.

    The American College of Medical Genetics state that testing for Factor V Leiden and prothrombin G20210 should be performed in at least the following circumstances: age >50 years, any venous thrombosis; venous thrombosis in unusual sites; recurrent venous thrombosis; venous thrombosis and a strong history of thrombotic disease; venous thrombosis in pregnant women or women taking oral contraceptives; relatives of individuals with venous thrombosis under age 50; MI in female smokers <50 years old. In addition, relatives of those with factor V Leiden or women with recurrent pregnancy loss or unexplained severe preeclampsia, placental abruption, intrauterine fetal growth retardation, or stillbirth.

  8. Kaufman AL, Spitz J, Jacobs, M, et al. Evidence for clinical implementation of pharmacogenetics in cardiac drugs. Mayo Clin Proc. 2015; 90(6): 716-729.
  9. Klerk M, et al. MTHFR 677C–>T polymorphism and risk of coronary heart disease: a meta-analysis. 2008; 288:2023-2031.

    Individuals who are compound heterozygotes for both the C677T and A1298C variants (~15-20% of individuals) have MTHFR activity reduced by 50-60%, and are at increased risk for hyperhomocysteinemia, deep vein thrombosis, and stroke.

Prediabetes/Diabetes

  1. Varvel SA, Pottala JV, Thiselton DL, et al. Serum α-hydroxybutyrate (α-HB) predicts elevated 1 h glucose levels and early-phase β-cell dysfunction during OGTT. BMJ Open Diabetes Res Care. 2014; 2(1):e000038

    In patients at increased risk for diabetes, fasting levels of alpha-hydroxybutyrate predicted elevated glucose levels at 1 hour during an oral glucose tolerance test.

  2. Cobb J, Eckhart A, Motsinger-Reif A, et al. α-Hydroxybutyric acid is a selective metabolite biomarker of impaired glucose tolerance. Diabetes Care. 2016; 39(6):988-995.

    The addition of alpha-hydroxybutyrate (α-HB), Linoleoyl-glycerophosphocholine (L-GPC), and oleic acid to age, sex, body mass index, and fasting glucose significantly improved prediction of impaired glucose tolerance in individuals without diabetes.

  3. Gall WE, Beebe K, Lawton KA, et al. alpha-hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population. PLoS One. 2010; 5(5):e10883.

    Alpha-hydroxybutyrate (α-HB) was shown to be a biomarker for both insulin resistance and impaired glucose regulation that may be used earlier than currently used clinical tests. 

  4. Varvel SA, Voros S. Thiselton DL, et al. Comprehensive biomarker testing of glycemia, insulin resistance, and beta cell function has greater sensitivity to detect diabetes risk than fasting glucose and HbA1c and is associated with improved glycemic control in clinical practice. J Cardiovasc Transl Res. 2014; 7:597-606.

    In this retrospective cohort study of 1687 US patients at risk for cardiovascular disease under routine clinical care, 45% of patients with normal glycemic indicators were demonstrated to have insulin resistance (IR) or beta-cell abnormalities. At follow-up, significantly more patients in the prediabetes and “high-normal” group (HbA1c 5.5 to 5.6) had improved than worsened symptoms. These findings suggest that for a significant proportion of patients, biomarker testing of IR and beta-cell dysfunction can enable early identification of IR in order to enable and inform treatment and improve glycemic control.

  5. Salomaa V, Havulinna A, Saarela O, et al. Thirty-one novel biomarkers as predictors for clinically incident diabetes. PLoS One. 2010; 5(4):e10100.

    This study identified novel biomarkers that were associated with the risk of clinically incident diabetes over and above the classic risk factors. The prediction of diabetes was improved by the addition of adiponectin, apolipoprotein B (apoB), ferritin, and C-reactive protein (CRP). These findings provide new insight into the pathogenesis of diabetes and may help improve prevention and treatment.

  6. Montonen J, Boeing H, Steffen A, et al. Body iron stores and risk of type 2 diabetes: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study. 2012; 55(10):2613-2621.

    Higher ferritin levels were associated with higher risk of type 2 diabetes. This association, in a case-control study of 27,548 individuals over a 7-year follow-up period, were shown to be independent of established diabetes risk factors.

  7. Juraschek SP, Steffes MW, Miller ER 3rd, Selvin E. Alternative markers of hyperglycemia and risk of diabetes. Diabetes Care. 2012; 35(11):2265-2270.

    Fructosamine and 1,5-AG were associated with incident diabetes risk, independent of baseline levels of HbA1c and fasting glucose.

  8. Reinstatler L, Qi YP, Williamson RS, Garn JV, Oakley GP Jr. Association of biochemical B12 deficiency with metformin therapy and vitamin B12 supplements. Diabetes Care. 2012; 35(2):327-333.

    This study of US adults shows that metformin use is commonly associated with vitamin B12 deficiency. The consequence of this higher prevalence of vitamin B12 deficiency (see next reference) mandates monitoring of B12 in those using metformin.

  9. Moore EM, Mander AG, Ames D, et al. Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care. 2013; 36(10):2981-2987.

    Patients with diabetes were shown to have worse cognitive performance than those without diabetes, a relationship that was associated with metformin use. Indeed, the odds of impaired cognitive performance with metformin use were 2-times higher than those for no use of metformin. Vitamin B12 and calcium supplements may alleviate metformin-induced vitamin B12 deficiency and were associated with better cognitive outcomes.

  10. Fournier JP, Yin H, Yu OH, Azoulay L. Metformin and low levels of thyroid-stimulating hormone in patients with type 2 diabetes mellitus. 2014; 186(15):1138-1145.

    In a longitudinal population-based study of patients, compared with sulfonylurea treatment, metformin monotherapy was associated with 55% increased risk of low TSH levels in patients with treated hypothyroidism, but not among those who were euthyroid. It is not widely recognized by clinicians that metformin use may lead to a decline in TSH levels in patients with treated hypothyroidism. Monitoring TSH levels among such patients is logical. See the articles by Reinstatler and Moore for other considerations for patients undergoing metformin therapy.

  11. Garvey WT, Kwon S, Zheng D, et al Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance. 2003; 52(2):453-462.

    The authors of this study concluded the following: 1) Insulin resistance had profound effects on lipoprotein size and subclass particle concentrations for VLDL, LDL, and HDL when measured by NMR; 2) In type 2 diabetes, the lipoprotein subclass alterations were moderately exacerbated but could be primarily attributed to the underlying insulin resistance; and 3) Insulin resistance–induced changes in the NMR lipoprotein subclass profile predictably increased the risk of cardiovascular disease.

  12. Malave H, Castro M, Burkle J, et al. Evaluation of Low-Density Lipoprotein Particle Number Distribution in Patients With Type 2 Diabetes Mellitus With Low-Density Lipoprotein Cholesterol < 50 mg/dL and Non-High-Density Lipoprotein Cholesterol < 80 mg/dL. Am J Cardiol. 2012; 110(5):660-665.

    Despite attaining LDL cholesterol <50 mg/dL or non-HDL cholesterol <80 mg/dL, patients with diabetes had significant variation in LDL particle levels, with most having LDL particle concentrations >500 nmol/L, suggesting residual risk for coronary heart disease.

  13. Fournier JP, Yin H, Yu OH, Azoulay L. Metformin and low levels of thyroid-stimulating hormone in patients with type 2 diabetes mellitus. 2014; 186(15):1138-1145.

    In a longitudinal population-based study of patients, compared with sulfonylurea treatment, metformin monotherapy was associated with 55% increased risk of low TSH levels in patients with treated hypothyroidism, but not among those who were euthyroid. It is not widely recognized by clinicians that metformin use may lead to a decline in TSH levels in patients with treated hypothyroidism. Monitoring TSH levels among such patients is logical. See the articles by Reinstatler and Moore for other considerations for patients undergoing metformin therapy.

Cardiometabolic/Metabolic/Other

  1. Patel D, Ahmad S, Silverman A, Lindsay J. Effect of cystatin C levels on angiographic atherosclerosis progression and events among postmenopausal women with angiographically decompensated coronary artery disease (from the Women’s Angiographic Vitamin and Estrogen [WAVE] Study). Am J Cardiol. 2013; 111(12):1681-1687.

    In this study of 423 postmenopausal women with angiographically documented coronary artery disease, those with the highest baseline cystatin C levels were more likely to have worse clinical outcomes (cardiovascular events, myocardial infarction, and cardiovascular and all-cause death), without accelerated progression of atherosclerosis.

  2. Schöttker B, Herder C, Müller H, Brenner H, Rothenbacher D. Clinical Utility of Creatinine-and Cystatin C–Based Definition of Renal Function for Risk Prediction of Primary Cardiovascular Events in Patients With Diabetes. Diabetes Care. 2012; 35(4):879–886.

    Among patients with diabetes and chronic kidney disease (CKD), the cystatin C–based definition of CKD was the only independent risk predictor for cardiovascular events. These findings suggest that cystatin C has better clinical utility for cardiovascular risk prediction than do creatinine-based equations.

  3. Veeranna V, Zalawadiya SK, Niraj A, et al. Homocysteine and reclassification of cardiovascular disease risk. J Am Coll Cardiol. 2011; 58(10):1025–33.

    From two disparate population cohorts (NHANES III and the Multiethnic Study of Atherosclerosis [MESA]), the authors found that addition of homocysteine level to the Framingham Risk Score significantly improved cardiovascular disease risk prediction, especially in individuals at intermediate risk for coronary heart disease events.

  4. Ueland PM, Loscalzo J. Homocysteine and cardiovascular risk: The perils of reductionism in a complex system. Clin Chem. 2012; 58(12):12:1623–1625.

    Plasma homocysteine is a predictor of cardiovascular disease in the general population and shows remarkable associations with a variety of risk factors, including lifestyle, nutrition, and disorders that affect cardiovascular health.

  5. Rodondi N, den Elzen WP, Bauer DC, et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. 2010; 304(12):1365-1374.

    In this meta-analysis of 11 prospective cohorts, subclinical hypothyroidism (a thyroid-stimulating hormone [TSH] level of 4.5 to 19.9 mIU/L) was associated with increased risk of coronary heart disease (CHD) events and CHD mortality in individuals with higher TSH levels, especially in those with TSH levels of 10 mIU/L or higher.

Autoimmune

  1. Theander E, Jonsson R, Sjostrom B, et al. Prediction of Sjögren’s Syndrome Years Before Diagnosis and Identification of Patients With Early Onset and Severe Disease Course by Autoantibody Profiling. Arthritis Rheumatol. 2015; 67(9):2427-2436. 

    Autoantibodies, including anti-nuclear antibody, rheumatoid factor, Sjögren’s antibody SS-A, and Sjögren’s antibody SS-B were detected in patients for 18 to 20 years before the diagnosis of primary Sjögren’s Syndrome (SS). The SS-A and SS-B antibodies were strongly associate with risk of primary SS and, in particular, with early-onset and severe disease.

  2. Kastbom A, Strandberg G, Lindroos A, Skogh T. Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project). Ann Rheum Dis. 2004; 63:1085-1089.

    Antibodies to cyclic citrullinated peptide (anti-CCP) have similar diagnostic sensitivity to rheumatoid factor, but are a better predictor of disease course over a 3-year period.

  3. Carmona-Fernandes D, Santos MJ, Canhao H, Fonseca JE. Anti-ribosomal P protein IgG autoantibodies in patients with systemic lupus erythematosus: diagnostic performance and clinical profile. BMC Med. 2013; 11:98.

    In this study of patients with systemic lupus erythematosus (SLE) or other rheumatic diseases, and healthy controls, anti-ribosomal P antibodies were demonstrated to have high specificity for SLE.

  4. Sugai E, Moreno ML, Hwang HJ, et al. Celiac disease serology in patients with different pretest probabilities: is biopsy avoidable?World J Gastroenterol. 2010; 16(25):3144-3152.

Cancer Testing

  1. Sullivan F & Schembri S. Progress with an RCT of the Detection of Autoantibodies to Tumour Antigens in Lung Cancer Using the Early CDT-Lung Test in Scotland (ECLS). J Thor Oncol. 2015; 10:S306.
  2. Jett JR, Peek LJ, Fredericks L, et al (2014) Audit of the autoantibody test, EarlyCDT-Lung, in 1600 patients: An evaluation of its performance in routine clinical practice. Lung Cancer. 2014; 83:51-55.
  3. Healey GF, Lam S, Boyle P, et al. Signal stratification of autoantibody levels in serum samples and its application to the early detection of lung cancer. J Thoracic Diseases. 2013; 5(5): 618-625.
  4. Aberle DR, DeMello S, Berg CD, et al. Results of the Two Incidence Screenings in the National Lung Screening Trial. N Engl J Med. 2013; 369:920-931.
  5. Chapman CJ, Healey GF, Murray A, et al. EarlyCDT®-Lung test: improved clinical utility through additional autoantibody assays. Tumor Biol. 2012; 33(5):1319-26.
  6. Pinsky PF and Berg CD. Applying the National Lung Screening Trial eligibility criteria to the US population: what percent of the population and of incident lung cancers would be covered? J Med Screen. 2012; 19(3):154-156.
  7. Boyle P, Chapman CJ, Holdenrieder S, et al. Clinical validation of an autoantibody test for lung cancer. Ann Oncol. 2011; 22(2):383-389.
  8. The National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011; 365:395-409.

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