Raising the standard: Unleashing the power of vitamin D testing through standardization

September 22, 2015

Raising the standard

Unleashing the power of vitamin D testing through standardization

As a lab leader, vitamin D is an important part of your future. Clinicians are continuously discovering its wellness benefits. But to take our knowledge to the next level, we need to be able to measure it more effectively—and consistently. To stay ahead of the curve, here’s a closer look at the topics you need to know, as well as how you can turn this challenge into an opportunity for your lab.

Disrupting care and progress

While the nature of lab testing is rapidly changing, one aspect remains constant—quality test results are foundational to minimizing cost and maximizing care. Yet as the number of lab tests multiplies, healthcare providers face an escalating issue. Substantial variation exists within and between these tests, which means substantial variation is likely to exist between the results. This undermines efforts to provide efficient and timely care.1-3

Variation doesn’t just affect patient results, but the outcomes of clinical trials. This impacts the value of the findings, in developing clinical guidelines and delivering evidence-based treatment. It could lead to further misdiagnoses, delayed diagnoses, or impractical /unnecessary courses of therapy. Inaccurate test results ultimately drive up research and healthcare costs, consume healthcare professionals’ time, and cause unnecessary patient suffering.

An extreme case of assay inconsistency: Vitamin D measurement

In recent years, great attention and scrutiny have been given to the measurement of vitamin D. This nutrient is essential, but its testing is highly flawed.

A closer look at vitamin D

Vitamin D acts like a hormone, and plays an essential biological function in the body. It helps to maintain concentrations of serum calcium and phosphorus, by helping the small intestine absorb these minerals from the diet.4 It plays a pivotal role in sustaining bone health, muscle strength, and immune function; regulating cellular differentiation; and reducing inflammation. Vitamin D may further help prevent a number of diseases, including type 1 and type 2 diabetes, hypertension, glucose intolerance, multiple sclerosis, and cancer.5

The renewed interest in vitamin D is largely due to the rise in vitamin D deficiency/insufficiency worldwide—estimated at 1 billion people5—as well as information linking deficiency to multiple clinical conditions beyond bone health.6 Specifically, since 1994, the number of Americans with levels under 30 ng/mL—the National Kidney Foundation threshold for insufficiency or deficiency—has doubled. These declining levels are associated with reduced consumption of milk that is fortified with vitamin D, decreased sun exposure, growing use of sunscreen, and increase in body mass index.6

"It doesn’t matter if you’re a healthy-looking infant or elderly, millions of Americans may be deficient in this essential nutrient."

Consequently, a multitude of new tests have been developed in the past few years to measure vitamin D levels. While manufacturers are continuously innovating for this growing market, many laboratories are developing their own tests to meet their needs. 

The problem for labs is that vitamin D is especially difficult to measure, which raises the risk of varied results. This may be due to differences in the measurement techniques, the way vitamin D is released from its binding proteins, or interference from heterophilic antibodies.7 With the application of new tests and platforms, it is critical for laboratorians to understand why they should test, what they should test for, and what criteria they should use to determine which test meets their needs.

"We need to craft more—and better controlled—disease causality studies related to vitamin D, and therefore need much more rigor in how we measure it.

Reaching standardized results through standardized testing

In 2007, variability in hormone testing reached a critical level. The CDC responded by initiating a venture to standardize hormone measurements. The objective was to improve diagnosis, treatment, and prevention of diseases and disorders through standardization. What they created was the Hormone Standardization Project (HoSt). This project would serve to issue standards for anchoring all test results, regardless of the method used. It would simultaneously minimize method bias and improve method precision.8

The CDC has even developed a certification program to gauge and certify the accuracy of vitamin D test methods on a yearly basis.6

The HoSt Project informs the proper use of hormone assays from before they leave the manufacturing plant to when they are in the hands of the end-users. It can even provide technical assistance for meeting performance standards, to facilitate long-term success in upholding standardization.8

Promoting the standards is vital to success

In 2010, a program was developed to communicate the CDC’s standardization process to clinicians everywhere. This program is called the Vitamin D Standardization Program (VDSP).9 It was established by the National Institutes of Health (NIH) Office of Dietary Supplements, in collaboration with the CDC, the National Institute for Standards and Technology (NIST) and Ghent University.6

The goal of the program is to uphold the standardization of vitamin D laboratory measurements worldwide, by comparing them to values obtained using reference measurement procedures (RMPs) developed at the NIST10 and Ghent University.11 An RPM is a laboratory method that conforms to the International Organization for Standardization guidelines. The VDSP is also embarking on an international research program to further improve the laboratory measurement process.

mapping the steps to standardization

The VDSP has outlined four steps to ensuring accurate and comparable measurement across testing systems and laboratories, over time. All assay manufacturers are encouraged to work with the VDSP to standardize their assays for optimal measurement.

Step 1: Develop a reference measurement system12

This is a set of components used to establish a calibration chain, from the values determined by an RMP to the laboratory.13 The system includes:

  • A definition of what is to be measured

  • RMPs and standard reference materials

  • Guidelines for assessing assay performance

  • A standardization certification program

  • Accuracy-based performance testing or external quality assessment schemes

  • Procedures for standardizing research results measured in the past

Step 2: Calibrate commercial assay systems to reference methods

Once developed, the reference measurement system can be used to link commercial assays to the reference methods. This is achieved using reference materials and single-donor serum samples with pre-assigned concentrations using the RMP.

Step 3: Calibrate individual clinical and research laboratory assays to reference methods

Individual assays are then compared to the reference methods. This establishes an unbroken chain of traceability between the RMP and laboratory assays.14 Routine assays are thereby standardized to the RMP for accurate measurement.

Step 4: Verify End-User Test Performance

User performance is then verified through the CDC certification program, to assure consistency across different assay types.15,16

Realizing a new standard

For many years, researchers, laboratory clinicians, and professional associations, such as The Endocrine Society, have spoken out about the unreliability of hormone measurements. Their concerns were so significant that key organizations even issued strong recommendations not to use certain hormone tests.8

Today, these concerns are being overturned. While standardized vitamin D measurement has not yet become the new norm, benefits are already being realized as a result of progress. More commercial manufacturers and labs are participating in certification and monitoring programs, and the CDC has even published a list of assays that have been standardization-approved.

This follows the course of previous standardization successes from the CDC and the NGSP, in areas such as HbA1c measurement for diabetes. According to the American Diabetes Association, HbA1c measurement has reached a pinnacle level of standardization and is now able to be used as a true diagnostic tool.

"Of particular importance, it is becoming increasingly recognized that tracing assay measurements to preset standards is vital to proper healthcare.

We can look to areas such as HbA1c measurement for practical examples of how fully implemented standardized testing can improve outcomes.

Standardized testing: benefits across stakeholders8

Laboratorians

  • A definition of what is to be measured

  • RMPs and standard reference materials

Physicians

  • Elevates confidence in health management

  • Facilitates the development of practical clinical guidelines

Patients

  • Facilitates proper diagnoses

  • Upholds the delivery of timely and appropriate care

Researchers

  • Ensures an accurate basis for clinical recommendations

  • Ensures test sensitivity and specificity to better determine biochemical causes of diseases

Public health scientists

  • Ensures an accurate basis for public health promotion and disease prevention efforts

  • Enables accurate evaluation of public health interventions and identification of individuals at risk for disease

Health insurers

  • Minimizes inconvenient and costly repeat testing

"Hopefully, in the next few years, we’ll have more information about disease causality and vitamin D— this is an essential step to getting there."

key standardization
steps you can take today

When you refine assay performance, you greatly enhance your ability to meet demands, enhance medical value, and strengthen your financial position.

You can start facilitating standardized results by confirming that all vitamin D assays are certified through the CDC Standardization Certification Program.

  • If you use commercial vitamin D assays: contact your representatives and find out if those assay manufacturers participate in the CDC program 

  • If you outsource vitamin D testing to a commercial clinical laboratory: contact the laboratory and find out if they participate in the CDC program

References: 1. Binkley N, Krueger D, Cowgill CS, et al. (2004). Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization. J Clin Endocrin Metab, 89(7), 3152-7. 2. Carter GD. (2011). Accuracy of 25‐hydroxyvitamin D assays: confronting the issues. Current Drug Targets, 12,19–28. 3. Lai JK, Lucas RM, Banks E, Ponsonby AL. Ausimmune Investigator Group. (2012). Variability in vitamin D assays impairs clinical assessment of vitamin D status. Intern Med J, 42, 43–50. 4. Holick MF. (2007). Vitamin D deficiency. N Engl J Med. 357(3), 266-281. 5. Office of Dietary Supplements, National Institutes of Health. (2014). Dietary Supplement Fact Sheet: Vitamin D. Retrieved from http://ods.od.nih.gov/factsheets/Vitamind-HealthProfessional. 6. Rose, AM. (2013). Vitamin D testing: clinical and laboratory considerations. Medical Laboratory Observer. Retrieved from http://www.mlo-online.com/articles/201305/vitamin-d-testing-clinical-and-laboratory-considerations.php. 7. Freeman, J, Wilson, K. (2013). Vitamin D progress toward standardization. Clinical Laboratory News. Retrieved from https://www.aacc.org/publications/cln/articles/2013/august/vitamin-d-standardization. 8. National Center for Environmental Health Division, Division of Laboratory Sciences, Centers for Disease Control and Prevention. Standardizing Hormone Measurements. Retrieved from http://www.cdc.gov/labstandards/pdf/hs/HoSt_Brochure.pdf. 9. Camara, C, Hoofnagle, A, Carter, C, Sempos, C. (2015). Take two: gearing up for the next vitamin D commutability study. Clinical Laboratory News. Retrieved from https://www.aacc.org/publications/cln/articles/2015/february/vitamin-d-commutability-study. 10. Tai SS, Bedner M, Phinney KW. (2010). Development of a candidate reference measurement procedure for the determination of 25‐hydroxyvitamin D3 and 25‐hydroxyvitamin D2 in human serum using isotope‐dilution liquid chromatography‐tandem mass spectrometry. Anal Chem, 82,1942–8. 11. Stepman HCM, Vanderroost A, Van Uytfanghe K, Thienpont LM. (2011). Candidate reference measurement procedures for serum 25‐hydroxyvitamin D3 and 25‐hydroxyvitamin D2 by using isotopedilution liquid chromatography‐tandem mass spectrometry. Clin Chem, 57, 441–8. 12. Bunk DM. (2007). Materials and reference measurement procedures: an overview from a national metrology institute. Clin Biochem Rev, 28, 131–7. 13. Myers GL. (2008). Introduction to standardization of laboratory results. Steroids, 73, 1293–6. 14. Miller WG, Myers GL, Gantzer ML, et al. (2011). Roadmap for harmonization of clinical laboratory measurement procedures. Clin Chem, 57, 1108–17. 15. Sempos CT, Vesper HW, Phinney KW, Thienpont LM, Coates PM. Vitamin D Standardization Program (VDSP). (2012). Vitamin D status as an international issue: national surveys and the problem of standardization. Scand J Clin Lab Invest Suppl, 243, 32–40. 16. Thienpont LM, Stepman HCM, Vesper HW. (2012) Standardization of measurements of 25‐hydroxyvitamin D3 and D2. Scand J Clin Lab Invest Suppl. 243, 41–9.

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