Genova Diagnostics offers nutritional/nutrient panel testing. Among the tests this company offers is NutrEval FMV, which involves analysis of urine and blood samples and provides information on more than 100 markers including organic acids, amino acids, fatty acids, markers of oxidative stress (direct measurement of glutathione and CoQ10, and markers of oxidative injury and DNA damage) and nutrient elements (see Table 1).^1,

Genova Diagnostics produces a report that includes test results categorized as normal, borderline, and high need, along with recommendations for supplements and dosages for items categorized as high need. NutrEval FMV patient reports can recommend supplementation or any of the nutrients listed in Table 1 if they are found to be areas of high need.

A related test, the ONE (Optimal Nutritional Evaluation) FMV also by Genova Diagnostics, limits testing to the organic acid, amino acid, and oxidative stress marker categories.

SpectraCell Laboratories offers a micronutrient test that measures functional deficiencies at the cellular level. The test assesses how well the body uses 33 vitamins, minerals, amino and fatty acids, antioxidants, and metabolites (see Table 1). SpectraCell categorizes test results into adequate, borderline, and deficient, and offers supplementation suggestions based on each patient’s deficiencies.

Table 1. Components of the NutrEval FMV Test

Category	NutrEval	SpectraCell Nutrient Testing
B vitamins	Thiamin B1, riboflavin B2, niacin B3, pyridoxine B6, biotin B7, folic acid B9, cobalamin B12	Vitamin A, vitamin B1, vitamin B2, vitamin B3, vitamin B6, vitamin B12, biotin, folate, pantothenate, vitamin C, vitamin D, vitamin K
Minerals	Magnesium, manganese, molybdenum, zinc	Calcium, magnesium, manganese, zinc, copper
Fatty acids	Omega-3-oils	Oleic acid
Digestive support	Probiotics, pancreatic enzymes
Other vitamins	Vitamin D
Amino acids	Arginine, asparagine, cysteine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, taurine, threonine, tryptophan, tyrosine, valine	Asparagine, glutamine, serine

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Nutrient/nutritional panel testing using urine and/or blood samples is offered (e.g., NutrEval FMV® and ONE FMV® by Genova Diagnostics; micronutrient testing by SpectraCell) under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

Related Policies

• Homocysteine Testing in the Screening, Diagnosis, and Management of Cardiovascular Disease and Venous Thromboembolic Disease (Policy #031 in the Pathology Section)
• Intracellular Micronutrient Analysis (Policy #068 in the Medicine Section)
• Cardiovascular Risk Panels (Policy #104 in the Pathology Section)

Nutrient/nutritional panel testing is considered investigational for all indications including but not limited to testing for nutritional deficiencies in members with mood disorders, fibromyalgia, unexplained fatigue, and healthy individuals.


Medicare Coverage:
Per LCD L34914, Micronutrient Testing for NUTRITIONAL deficiencies that include multiple tests for vitamins, minerals, antioxidants and various metabolic functions are never necessary. Vitamin or micronutrient testing may not be used for routine screening. Once a beneficiary has been shown to be vitamin deficient, further testing is medically necessary only to ensure adequate replacement has been accomplished. Thereafter, annual testing may be appropriate depending upon the indication and other mitigating factors. For additional information and eligibility, refer to: Local Coverage Determination (LCD): Assays for Vitamins and Metabolic Function (L34914). https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=34914&ver=48&Keyword=nutritional+test&KeywordSearchType=Or&Date=&PolicyType=Both&ArticleType=SAD%7cEd&Cntrctr=323*1&KeyWordLookUp=Doc&SearchType=Advanced&CoverageSelection=Both&kq=true&bc=IAAAACAAAAAAAA%3d%3d&.

The following TESTs are considered non-covered services:
• Assays of selenium (84255)
• Functional intracellular analysis (84999)
• Functional intracellular analysis or total antioxidant function (84999)
• Assays of vitamin testing, not otherwise classified* (84591)

For additional information and eligibility, refer to Local Coverage Article: Billing and Coding: Assays for Vitamins and Metabolic Function (A56416). Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/LcdSearch?_afrLoop=90769712476969#!%40%40%3F_afrLoop%3D90769712476969%26centerWidth%3D100%2525%26leftWidth%3D0%2525%26rightWidth%3D0%2525%26showFooter%3Dfalse%26showHeader%3Dfalse%26_adf.ctrl-state%3D63y7eftob_46.


[RATIONALE: This policy was created in 2015 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through October 14, 2019.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Nutrient/Nutritional Panel Testing

Clinical Context and Test Purpose

The purpose of nutrient/nutritional panel testing in patients who have mood disorders, fibromyalgia, or unexplained fatigue or in healthy individuals seeking to optimize health and fitness is to inform a decision whether the patient might benefit from specific nutrient supplementation.

The question addressed in this policy is: Does the use of nutrient/nutritional panel testing, to identify nutrient deficiencies, result in improved health outcomes among patients with mood disorders, fibromyalgia, or unexplained fatigue or among healthy individuals seeking to optimize health and fitness compared with standard of care.

The following PICOs were used to select literature to inform this policy.

Patients

The relevant populations of interest are patients with mood disorders, fibromyalgia, or unexplained fatigue, or healthy individuals seeking to optimize health and fitness.

Interventions

The relevant intervention of interest is nutrient/nutritional panel testing.

Ordering and interpreting nutrient/nutritional panel testing should be done by physicians in an outpatient or inpatient setting.

Comparators

The following practice is currently being used to manage mood disorders, fibromyalgia, unexplained fatigue, or healthy individuals seeking to optimize health and fitness: standard of care.

Outcomes

The potential beneficial outcomes of primary interest would be an improvement in symptoms, change in disease status, and functional outcomes. The potential harmful outcomes are those resulting from a false test result. False-positive or false-negative test results can lead to the initiation of unnecessary treatment and adverse events from that overtreatment or undertreatment.

Nutrient/nutritional panel testing might be conducted before or after starting specific therapy for the specific conditions addressed herein or as a screening test for healthy individuals seeking to optimize health and fitness.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess the clinical validity of nutrient/nutritional panel testing to evaluate patients with mood disorders, fibromyalgia, or unexplained fatigue, or among healthy individuals seeking to optimize health and fitness, studies should report sensitivity, specificity, positive and negative predictive values. Additionally, studies reporting false-positive rates and false-negative rates are informative.
• To assess the clinical utility of nutrient/nutritional panel testing to evaluate the conditions listed above, studies should demonstrate how the results of the panel tests impacted treatment decisions and the overall management of the patient.

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

No RCTs were identified that assessed the clinical utility of nutrient/nutritional panel testing for mood disorders, fibromyalgia, chronic fatigue, or optimization of health and fitness.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

The chain of evidence to support the clinical utility of the use of nutrient/nutritional panel testing would consist of: (1) evidence that specific nutritional deficiencies included in the panel test are significantly associated with mood disorders, fibromyalgia, and/or chronic fatigue; (2) evidence that, in patients with mood disorders, fibromyalgia, and/or chronic fatigue, treatment of a patient found to have specific nutritional deficiencies (e.g., with nutritional supplements) improves health outcomes; and (3) evidence that, if there is sufficient evidence on the first two items, panel testing is more appropriate than testing for specific nutrients.

Mood Disorders, Fibromyalgia, or Unexplained Fatigue

Several systematic reviews and meta-analyses evaluating associations between the indications of interest and specific nutrient deficiencies were identified, and they are described in Table 2. No systematic reviews or meta-analyses were identified in the association between nutritional deficiencies and unexplained fatigue. A limitation of all reviews is that, although they compared low and high levels of nutrient levels, none addressed whether these low levels constituted actual deficiencies in a particular nutrient.

Table 2. Systematic Reviews on the Association Between Nutritional Deficiencies and Mood Disorders, Fibromyalgia, and Unexplained Fatigue

Study	Nutrient	No. of Studies	Specified Cutoff for Nutrient Deficiency	Key Findings (95% CI)
Depression
Petridou et al (2015)2,	Folate and vitamin B12	11	No	Odds of having depression significantly associated with low folate and vitamin B levels: · Folate: OR=1.27 (1.07 to 1.43) · Vitamin B: OR=1.20 (1.02 to 1.42)
Cheungpasitporn et al (2015)3,	Magnesium	6	No	Pooled RR of depression in patients with hypomagnesemia (3 cohort studies, 2 cross-sectional studies, 1 case-control study combined; N=19,137 patients): · 1.34 (1.01 to 1.79; I2=33%) Pooled RR excluding the cross-sectional studies: · 1.38 (0.92 to 2.07; I2=24%)
Swardfager et al (2013)4,	Zinc	17	No	Mean serum zinc concentrations of -1.85 ìmol/L (-2.52 to -1.19 ìmol/L) in depressed patients vs nondepressed controls (p<0.001)
Anglin et al (2013)5,	Vitamin D	14	No	Cross-sectional studies: · OR of depression, highest vs lowest vitamin D categories: 1.31 (1.00 to 1.71; p=0.03) Prospective series: · Risk of depression significantly higher in patients with lower vitamin D (HR=2.21; 1.40 to 3.49; p=0.028)
Fibromyalgia
Hsiao et al (2015)6,	Vitamin D	12	No	Significantly higher odds of hypovitaminosis D among patients with chronic pain including fibromyalgia vs control group: · Crude OR=1.63 (1.20 to 2.23) · Adjusted OR=1.41 (1.00 to 2.00)
Daniel and Pitotta (2011)7,	Vitamin D		No	No pooled analyses. Lower-quality studies tended to find positive associations between fibromyalgia and low vitamin D levels; studies with control groups found no significant associations; larger population-based studies had mixed findings

CI: confidence interval; HR: hazard ratio; OR: odds ratio; RR: relative risk.

Subsection Summary: Mood Disorders, Fibromyalgia, or Unexplained Fatigue

Evidence from multiple systematic reviews and meta-analyses of observational studies have indicated an association between deficiency of nutrients (vitamin B₁₂, vitamin D, folate, magnesium, zinc) and different outcomes (depression, fibromyalgia). There is no evidence whether screening for these nutrient deficiencies results in improved health outcomes compared with no screening.

Treatment of Mood Disorders, Fibromyalgia, or Unexplained Fatigue in Patients with Nutritional Deficiencies

Several systematic reviews and meta-analyses evaluating health outcomes in patients with depression treated with nutritional supplementation were identified, and they are described in Table 3. A limitation of all of the reviews is that they did not require patients to have an established deficiency of any nutrient. No systematic reviews or meta-analyses were identified on nutritional interventions in patients with fibromyalgia or unexplained fatigue.

Table 3. Systematic Reviews on Interventions for Patients with Mood Disorders, Fibromyalgia, and/or Unexplained Fatigue Diagnosed with Nutritional Deficiencies

Study	Intervention and Comparator	No. and Type of Studies	Patients Diagnosed With Nutritional Deficiencies	Key Findings (95% CI)
Depression
Gowda et al (2015)8,	Vitamin D	9 RCTs	·No in overall analysis ·Yes in subgroup analysis	· No significant difference found in depression after supplementation with vitamin D vs placebo (SMD=0.28; -0.14 to 0.69) · No significant difference found in depression with vitamin D vs placebo in patients with baseline vitamin D >50 nmol/L or in patients with baseline vitamin D <50 nmol/L
Taylor et al (2003)9,	Folic acid (alone or as adjunctive treatment) vs antidepressant medication	3 RCTs	No	Difference in HDRS scores significantly lower in patients taking folic acid plus antidepressants vs antidepressants alone (MD= -2.65; -4.93 to -0.038)

CI: confidence interval; HDRS: Hamilton Depression Rating Scale; MD: mean difference; RCT: randomized controlled trial; SMD: standard mean difference.

Nowak et al (2016) conducted a single-center, double-blind, placebo-controlled trial to determine whether a single vitamin D dose would reduce fatigue after 30 days among 120 otherwise healthy persons with low serum 25-hydroxyvitamin D levels (mean age, 29 years; 53% women).^10, The outcome was measured using the Fatigue Assessment Scale. The vitamin D group had a significantly greater decrease in mean (standard deviation) Fatigue Assessment Scale score (-3.3, standard deviation=5.3) than the placebo group (-0.8, standard deviation=5.3; p=0.01). Improvements were reported more frequently in the vitamin D group (42 [72%]) than in placebo group (31 [50%]; p=0.01; odds ratio, 2.63; 95% confidence interval for odds ratio, 1.23 to 5.62). Among all participants, improvement in the Fatigue Assessment Scale correlated with the rise in 25-hydroxyvitamin D levels (r=0.22, p=0.02).

Subsection Summary: Treatment of Mood Disorders, Fibromyalgia, or Unexplained Fatigue in Patients with Nutritional Deficiencies

A systematic review and meta-analysis of RCTs have suggested that folate might have a role as a supplement to other therapies in patients with depression. However, it is unclear whether folate supplement would benefit both people with normal folate levels and those with folate deficiency. A meta-analysis of RCTs has suggested no significant benefit of vitamin D supplementation vs placebo in the case of depression. There is no evidence whether screening for these nutrient deficiencies (vs no screening) would result in significant improvement in outcomes.

Panel Testing vs Testing for Individual Nutrients

There is no evidence on any indication to suggest that nutritional panel testing improves the net health outcome compared with testing for one or several individual nutrients. This includes patients with mood disorders, fibromyalgia, and/or unexplained fatigue, as well as healthy individuals seeking to optimize health and/or fitness. Moreover, with nutritional panel testing, there is a potential for incidental findings that could cause harm. Examples of potential harms include unnecessary confirmatory tests, unnecessary treatments provided for clinically insignificant conditions, and toxicity related to supplementation, or interactions between nutritional supplements and prescription medication.

Summary of Evidence

For individuals who have mood disorders, fibromyalgia, or unexplained fatigue, or healthy individuals who seek to optimize health and fitness who receive nutritional panel testing, the evidence includes several systematic reviews on the association between a single condition and a single nutrient and on the treatment of specific conditions with nutritional supplements. The relevant outcomes are symptoms, change in disease status, and functional outcomes. There was no evidence of associations between fibromyalgia or unexplained fatigue and nutrient deficiencies. Systematic reviews have found statistically significant associations between depression and levels of several nutrients; however, there is no evidence that nutrient supplementation for patients with depression improves health outcomes. Also, there is no direct evidence on the health benefits of nutritional panel testing for any condition, including testing healthy individuals, and no evidence that nutritional panel testing is superior to testing for individual nutrients for any condition. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

No guidelines or statements were identified.

U.S. Preventive Services Task Force Recommendations

The U.S. Preventive Services Task Force has not addressed nutritional panel testing. The Task Force has made several recommendations addressing screening for individual nutrients. The Task Force concluded that there is insufficient evidence to recommend for or against screening for iron deficiency anemia in asymptomatic children and vitamin D deficiency in asymptomatic adults.^11,12, Screening for iron deficiency anemia is recommended in asymptomatic pregnant women.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in October 2019 did not identify any ongoing or unpublished trials that would likely influence this review.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Nutrient/Nutritional Panel Testing
Nutrient Panel Testing
Nutritional Panel Testing
NutriEval FMV
NutrEval FMV
ONE FMV
Optimal Nutritional Evaluation FMV

References:
1. Genova Diagnostics. NutrEval FMV. 2015; https://www.gdx.net/product/nutreval-fmv-nutritional-test-blood-urine. Accessed November 11, 2019.

2. Petridou ET, Kousoulis AA, Michelakos T, et al. Folate and B12 serum levels in association with depression in the aged: a systematic review and meta-analysis. Aging Ment Health. Jun 8 2015:1-9. PMID 26055921

3. Cheungpasitporn W, Thongprayoon C, Mao MA, et al. Hypomagnesaemia linked to depression: a systematic review and meta-analysis. Intern Med J. Apr 2015;45(4):436-440. PMID 25827510

4. Swardfager W, Herrmann N, Mazereeuw G, et al. Zinc in depression: a meta-analysis. Biol Psychiatry. Dec 15 2013;74(12):872-878. PMID 23806573

5. Anglin RE, Samaan Z, Walter SD, et al. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry. Feb 2013;202:100-107. PMID 23377209

6. Hsiao MY, Hung CY, Chang KV, et al. Is serum hypovitaminosis D associated with chronic widespread pain including fibromyalgia? A meta-analysis of observational studies. Pain Physician. Sep-Oct 2015;18(5):E877-887. PMID 26431141

7. Daniel D, Pirotta MV. Fibromyalgia--should we be testing and treating for vitamin D deficiency? Aust Fam Physician. Sep 2011;40(9):712-716. PMID 21894281

8. Gowda U, Mutowo MP, Smith BJ, et al. Vitamin D supplementation to reduce depression in adults: meta-analysis of randomized controlled trials. Nutrition. Mar 2015;31(3):421-429. PMID 25701329

9. Taylor MJ, Carney S, Geddes J, et al. Folate for depressive disorders. Cochrane Database Syst Rev. Jun 2003(2):CD003390. PMID 12804463

10. Nowak A, Boesch L, Andres E, et al. Effect of vitamin D3 on self-perceived fatigue: A double-blind randomized placebo-controlled trial. Medicine (Baltimore). Dec 2016;95(52):e5353. PMID 28033244

11. U.S. Preventive Services Task Force (USPSTF). Iron Deficiency Anemia: Screening. 2006; https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/iron-deficiency-anemia-screening. Accessed November 11, 2019.

12. U.S. Preventive Services Task Force (USPSTF). Vitamin D Deficiency: Screening. 2014; https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/vitamin-d-deficiency-screening. Accessed November 11, 2019.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*
[There are no specific codes for these panels of tests. Tests in the panel that have specific CPT codes would be reported using those codes.]

HCPCS

* CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.
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Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.

The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy
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