CurrentHealthfirstPolicy PO-RE-006v4

Vitamin B12 and Methylmalonic Acid Testing

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Defines coverage criteria for serum total vitamin B12 and methylmalonic acid (MMA) testing, including indications, limitations, and tests that do not meet coverage criteria; applies to Healthfirst members as described in the policy.

Policy Summary

PayerHealthfirst

PolicyVitamin B12 and Methylmalonic Acid Testing

Policy CodePolicy PO-RE-006v4

Change TypeNo material change

Effective DateMay 1, 2025

Last ReviewMar 16, 2026

Next Review DateN/A

Key ActionOrder serum total vitamin B12 (with CBC) and, if serum B12 is low‑normal or clinical suspicion persists, obtain serum methylmalonic acid (MMA) to confirm deficiency.

SourceLink

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CurrentHealthfirstPolicy PO-RE-006v4

Vitamin B12 and Methylmalonic Acid Testing

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Policy Summary

PayerHealthfirst

PolicyVitamin B12 and Methylmalonic Acid Testing

Policy CodePolicy PO-RE-006v4

Change TypeNo material change

Effective DateMay 1, 2025

Last ReviewMar 16, 2026

Next Review DateN/A

Key ActionOrder serum total vitamin B12 (with CBC) and, if serum B12 is low‑normal or clinical suspicion persists, obtain serum methylmalonic acid (MMA) to confirm deficiency.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

every 3 monthsfrequency (total B12)

MMA second-lineMMA role

not coveredholoTC stance

not coveredhomocysteine stance

>95%MMA sensitivity

Coverage Criteria

inv-01: Covered: Total vitamin B12

Total vitamin B12 (serum cobalamin) testing MEETS COVERAGE CRITERIA once every three months when ANY of the following groups apply:

Covered indications for total vitamin B12: Any of: (1) individuals with listed signs and symptoms of vitamin B12 deficiency (cutaneous, gastrointestinal, hematologic, neuropsychiatric), OR (2) individuals undergoing treatment for vitamin B12 deficiency, OR (3) individuals with one or more risk factors for vitamin B12 deficiency (decreased ileal absorption, decreased intrinsic factor, transcobalamin II deficiency, inadequate intake, prolonged medication use).once every three months

Signs/symptoms and risk factor lists are enumerated in the policy (see supporting chunks)

inv-02: Covered: Methylmalonic acid testing

Methylmalonic acid (MMA) testing MEETS COVERAGE CRITERIA when:

Covered indications for MMA: MMA testing is covered in asymptomatic high-risk individuals with low-normal vitamin B12 or when vitamin B12 deficiency is suspected but the serum vitamin B12 level is normal or low-normal. MMA testing also meets coverage for evaluation of inborn errors of metabolism.not specified

Policy states MMA is a preferred confirmatory/metabolic marker in these scenarios; elevated MMA sensitivity reported >95%

inv-03: Not covered — Tests and uses that DO NOT MEET COVERAGE CRITERIA

Tests and uses that DO NOT MEET COVERAGE CRITERIA:

Not covered tests/uses: Screening in healthy, asymptomatic individuals; homocysteine testing for confirmation of vitamin B12 deficiency; holotranscobalamin testing for screening, testing, or confirmation of vitamin B12 deficiency; total vitamin B12 testing for situations not described in the covered indications (see CC7).not applicable

Listed explicitly in the policy

inv-04: Medically Necessary Indications

Covered when ANY of the following indication groups apply (aligns with cited specialty guidance):

Symptomatic patients: Patients presenting with suspected clinical manifestations of B12 deficiency (neurologic such as paresthesia, gait abnormalities, loss of vibration/proprioception, cognitive impairment, optic/visual disturbances; hematologic abnormalities including macrocytic or megaloblastic anemia, leukopenia, thrombocytopenia; glossitis; unexplained fatigue), OR abnormal CBC suggesting anemia/macrocytosis.

Supported by AAFP and NICE clinical symptom lists

High-risk patients: Patients with risk factors including malabsorptive disorders (Crohn disease, ileal resection), prior or planned bariatric surgery, pernicious anemia or decreased intrinsic factor (atrophic gastritis, post-gastrectomy), transcobalamin II deficiency, long-term metformin use, prolonged H2-blocker or PPI use, elderly (>75), strict vegetarians/vegans, eating disorders, or other conditions causing inadequate intake or malabsorption.

Supported by AAFP, ASMBS, NICE, Vitamin B12 Consensus Panel

Perioperative bariatric surgery monitoring: Preoperative screening for vitamin B12 is recommended for all bariatric surgery candidates; post-operative baseline and more frequent monitoring in the first year (e.g., every 3 months), then at least annually; include MMA where serum B12 may be inadequate.

inv-05: Documented criteria revision (Dec 2024)

Noted historical/administrative criteria changes (excerpt):

Three-month testing frequency added: A three-month testing frequency for all vitamin B testing/screening was added in the 12/04/2024 revision, resulting in a main criterion that total vitamin B12 (serum cobalamin) testing MEETS COVERAGE CRITERIA once every three months for specified situations and the addition of a new CC7 designating other situations as not meeting coverage criteria.once every 3 months

Document indicates this change modified criterion structure and added CC7 (not-covered clause)

Screening for vitamin B12 deficiency in healthy, asymptomatic individuals DOES NOT MEET COVERAGE CRITERIA. The policy explicitly lists screening of asymptomatic, healthy persons as a use that is not covered and should not be ordered as routine population screening.

Routine screening of asymptomatic, average-risk individuals is not supported by guideline-based evidence and is not indicated. The AAFP does not recommend screening persons at average risk, and regional guidance (The Doctors of BC) likewise states routine screening and testing in asymptomatic patients is not supported.

The December 4, 2024 revision added a default exclusion (CC7): for all other situations not described in the enumerated covered criteria, total vitamin B12 (serum cobalamin) testing DOES NOT MEET COVERAGE CRITERIA. This change also introduced a three-month testing frequency for covered vitamin B testing.

Holotranscobalamin testing and homocysteine testing are explicitly designated as not meeting coverage when used for screening, testing, or confirmation of vitamin B12 deficiency. Specifically, holotranscobalamin testing DOES NOT MEET COVERAGE CRITERIA for screening, testing, or confirmation, and homocysteine testing DOES NOT MEET COVERAGE CRITERIA for confirmation of deficiency.

Testing as routine population screening in asymptomatic, average-risk patients is not supported and therefore is not covered. Providers should reserve vitamin B12 or confirmatory metabolic testing for patients with risk factors or suspected clinical manifestations rather than ordering B12 tests for screening of average-risk, asymptomatic individuals.

Per the December 4, 2024 revision, testing that falls outside the specifically enumerated covered situations (the listed clinical indications) is designated as not meeting coverage under the newly added clause (CC7). The same revision instituted a once every three months frequency for covered total vitamin B12 testing.

Covered Indications

inv-32: Serum total vitamin B12 testing

Meets coverage once every three months for listed signs/symptoms, risk factors, and during treatment:

Serum total vitamin B12 testing — covered situations: Total vitamin B12 (serum cobalamin) testing is covered once every three months for: (a) individuals with signs/symptoms of B12 deficiency (cutaneous: hyperpigmentation, jaundice, vitiligo; gastrointestinal: glossitis; hematologic: anemia, leukopenia, pancytopenia, thrombocytopenia, thrombocytosis; neuropsychiatric: areflexia, cognitive impairment, gait abnormalities, irritability, loss of proprioception and vibratory sense, olfactory impairment, peripheral neuropathy), (b) individuals undergoing treatment for B12 deficiency, and (c) individuals with listed risk factors (decreased ileal absorption, decreased intrinsic factor, transcobalamin II deficiency, inadequate intake including age >75, vegans, alcohol abuse, eating disorder, or prolonged medication use such as H2 blockers, metformin, or PPIs).once every three months

Derived from policy sections enumerating covered signs/symptoms and risk factors

inv-33: Serum methylmalonic acid (MMA) testing

Meets coverage when used to clarify equivocal serum B12 or in asymptomatic high-risk individuals:

Frequency and Monitoring Limits

inv-37: Total vitamin B12 (serum cobalamin) — once every three months

TestTotal vitamin B12 (serum cobalamin)

Allowed frequencyOnce every three months

Covered situationsIndividuals with signs/symptoms, undergoing treatment, or with one or more risk factors for B12 deficiency

inv-38: Vitamin B12 (with MMA optional/conditional) — every 3 months initially, then at least annually

TestVitamin B12 (with MMA optional/conditional)

Initial frequencyEvery 3 months initially (e.g., post-bariatric surgery first year)

Long-term frequency

Provider Actions and Guidance

Prior Authorization

Coverage frequency and indications — limit B12 testing to every 3 months for covered indications

Total vitamin B12 (serum cobalamin) testing meets coverage criteria once every three months for individuals with listed signs/symptoms, those undergoing treatment for B12 deficiency, or those with one or more risk factors for deficiency; document the clinical indication and limit repeat testing to the three-month frequency for covered situations.

Apply the once-every-3-months frequency only when one of the covered indications is present (signs/symptoms, treatment monitoring, or risk factors).
Document the specific sign/symptom, treatment status, or risk factor in the medical record when ordering the test.

Documentation Required

Bariatric surgery-related testing — pre-op screening and post-op monitoring with documentation

Perform preoperative screening for all patients undergoing metabolic/bariatric surgery and routine postoperative monitoring (more frequent in the first year, e.g., every 3 months, then at least annually); when ordering, document surgical history and the risk indications.

Coding

Applicable CPT/chemistry codesCPT

82607	Cyanocobalamin (Vitamin B-12)
83090	Homocysteine
83921	Organic acid, single, quantitative
84999	Unlisted chemistry procedure

Ordering Requirements

Documentation Required

ORDERING REQUIREMENTS — start with CBC and serum B12; use MMA when indicated

Order testing following AAFP guidance: begin with a CBC and serum vitamin B12 and proceed to MMA when serum B12 is normal or low-normal but clinical suspicion remains or macrocytosis is present.

Document CBC results and clinical findings that prompt escalation to MMA as part of the order.
Use MMA as the preferred metabolic confirmatory test when indicated.

Documentation Required

ORDERING REQUIREMENTS — document clinical context and consider pre-treatment sampling

Include relevant clinical context (symptoms, risk factors, surgical history, CBC results) when ordering tests and consider pre-treatment sampling for metabolic testing when indicated.

For MMA or metabolic evaluations, document why pre-treatment samples are needed and that samples were collected prior to therapy.
Record bariatric surgery status and medication history (e.g., metformin, PPIs) when relevant.

Not Covered

Holotranscobalamin testing for screening, testing, or confirmation of vitamin B12 deficiency and homocysteine testing for confirmation are listed among tests that DO NOT MEET COVERAGE CRITERIA. Additionally, routine population screening in healthy asymptomatic individuals is not covered; orders lacking clinical indication or relevant risk factors may be denied.

Routine B12 screening in asymptomatic, average-risk patients is not supported by guideline recommendations and is not covered. The AAFP and The Doctors of BC both advise against routine screening in average-risk asymptomatic persons.

Total vitamin B12 (serum cobalamin) testing for situations not described in the policy's enumerated covered criteria (per the December 4, 2024 revision, designated as CC7) DOES NOT MEET COVERAGE CRITERIA. Providers should document that orders match one of the listed covered indications to avoid noncoverage.

Definitions and Biomarkers

inv-26: Methylmalonic acid (MMA) — A metabolite produced from excess methylmalonyl-CoA that accumulates when vitamin B12 is unavailable and indicates functional deficiency

DefinitionMethylmalonic acid (MMA) is a metabolite produced from excess methylmalonyl‑CoA that accumulates when vitamin B12 is unavailable and indicates functional B12 deficiency

Clinical roleUsed as an adjuvant diagnostic/second‑line test to confirm suspected cobalamin deficiency

Analytical noteElevated serum MMA sensitivity for overt cobalamin deficiency reported >95% (specificity not fully determined)

inv-27: Holotranscobalamin (holoTC) — The metabolically active fraction of vitamin B12, an emerging marker of impaired vitamin B12 status

DefinitionHolotranscobalamin (holoTC) is the metabolically active fraction of vitamin B12

Clinical status

Background

Vitamin B12 (cobalamin) is essential for red blood cell formation, neurological function, and DNA synthesis. When vitamin B12 is unavailable, methylmalonic acid (MMA) accumulates, making MMA a useful metabolic indicator of functional B12 deficiency. Holotranscobalamin represents the metabolically active fraction of B12 and is an emerging marker but is not covered for screening or confirmation in this policy.

Revision History

2025-12-03review_updateLatest

Reviewed and updated background, guidelines, recommendations, and evidence-based references; literature review did not require changes to coverage criteria.

2024-12-04coverage_change

Added a three-month testing frequency for all vitamin B testing/screening, creating a main criterion that total vitamin B12 (serum cobalamin) testing meets coverage criteria once every three months for specified situations and adding a new CC7 that designates other situations as not meeting coverage criteria.

Policy Summary

PayerHealthfirst

PolicyVitamin B12 and Methylmalonic Acid Testing

Policy CodePolicy PO-RE-006v4

Change TypeNo material change

Effective DateMay 1, 2025

Last ReviewMar 16, 2026

Next Review DateN/A

Key ActionOrder serum total vitamin B12 (with CBC) and, if serum B12 is low‑normal or clinical suspicion persists, obtain serum methylmalonic acid (MMA) to confirm deficiency.

SourceLink

On This Page

Supported by ASMBS and BOMSS perioperative guidance

Equivocal serum B12 or discordant findings: When serum vitamin B12 is normal or low-normal but clinical suspicion persists or CBC shows macrocytosis, measure serum MMA (or total homocysteine if MMA unavailable) as a second-line test to assess metabolic deficiency.

Supported by AAFP and Vitamin B12 Consensus Panel recommendations

Monitoring treatment or absorption: Use MMA to monitor treatment effectiveness and success of oral therapy when absorption or dosing is uncertain; measure MMA (or homocysteine if MMA unavailable) as indicated.

Supported by Vitamin B12 Consensus Panel guidance

Serum methylmalonic acid (MMA) testing — covered situations: Serum MMA testing meets coverage in asymptomatic high-risk individuals with low-normal vitamin B12, when vitamin B12 deficiency is suspected despite normal/low-normal serum B12, and for the evaluation of inborn errors of metabolism. MMA is a preferred metabolic confirmatory test in these scenarios with reported sensitivity >95%.not specified

Policy and cited evidence identify MMA as preferred second-line/metabolic marker

inv-34: Suspected vitamin B12 deficiency based on clinical signs/symptoms or abnormal CBC and high-risk individuals

Initial evaluation and follow-up testing sequence for suspected deficiency:

Initial evaluation for suspected vitamin B12 deficiency should include a complete blood count (CBC) and serum vitamin B12 level.

AAFP recommends CBC + serum B12 as first-line

Second-line testing when indicated: If serum B12 is low or low-normal, or clinical suspicion persists despite a normal/low-normal serum B12 (including macrocytosis on CBC), perform serum MMA (or total homocysteine if MMA is unavailable) to assess metabolic B12 deficiency.

Supported by AAFP and Vitamin B12 Consensus Panel

inv-35: Preoperative and postoperative bariatric surgery screening and monitoring

Perioperative and postoperative bariatric surgery screening and monitoring:

Preoperative screening: Routine preoperative screening for vitamin B12 is recommended for all patients undergoing metabolic/bariatric surgery.

ASMBS recommends routine pre-WLS screening

Postoperative monitoring should include baseline and more frequent testing in the first post-operative year (e.g., every 3 months), then at least annually; consider measuring MMA with or without homocysteine when serum B12 may be inadequate.initially every 3 months, then at least annually

ASMBS guidance recommends more frequent early monitoring and inclusion of MMA

inv-36: Symptoms or risk factors suggestive of vitamin B12 deficiency

Symptoms and risk factors that support testing:

Symptoms indicative of B12 deficiency: Symptoms include abnormal blood count findings (anemia, macrocytosis), cognitive difficulties, visual disturbances/optic neuropathy, glossitis, peripheral neuropathy, gait/balance impairment, pins and needles or numbness, unexplained fatigue, and other neurologic signs (areflexia, loss of proprioception).

Derived from NICE and AAFP symptom lists

Risk factors that support testing: Risk factors include diets low in B12 (vegans/strict vegetarians), malabsorptive conditions, bariatric surgery history, pernicious anemia/atrophic gastritis, long-term use of medications associated with B12 deficiency (metformin, H2 blockers, PPIs, colchicine, anticonvulsants), advanced age, eating disorders, and socioeconomic or feeding barriers affecting intake.

Derived from NICE, AAFP, and consensus guidance

Then at least annually

Conditional testingMeasure serum MMA (or homocysteine if MMA unavailable) when B12 is low/low‑normal or clinical suspicion persists

inv-39: Vitamin B12 — periodic (e.g., annually)

TestVitamin B12 (serum cobalamin)

Suggested periodic monitoringPeriodic monitoring (e.g., annually) for chronic risk groups such as long‑term metformin users

Use caseDetect deficiency prior to clinical manifestation and guide management

inv-40: Dec 2024 revision frequency — total vitamin B12 and broadly 'all vitamin B testing/screening' once every 3 months

Revision date12/04/2024 (documented in revision history)

Policy changeAdded a three‑month testing frequency for all vitamin B testing/screening

Operational effectTotal vitamin B12 (serum cobalamin) testing MEETS COVERAGE CRITERIA once every 3 months for specified situations; new CC7 states testing outside enumerated situations does not meet coverage

Include MMA testing where serum B12 may be inadequate or to evaluate suspected deficiency pre- or post-operatively.
Record the type of bariatric procedure and timing relative to surgery in the order documentation.

Billing Rule

Prior authorization and code applicability — follow Healthfirst coding and payer rules

Submit claims using the applicable procedure codes and follow Healthfirst coding and reimbursement rules; prior authorization requirements, if any, are determined by the member's evidence of coverage and provider participation agreement.

Relevant codes listed in the policy include 82607, 83090, 83921, and 84999 — use appropriate CPT/HCPCS coding guidance when billing.
Verify prior authorization requirements per payer rules and the member's coverage before performing non-emergent testing.

Step Therapy

Preferred testing sequence — CBC and serum B12 first, then MMA if indicated

Start the diagnostic workup with a complete blood count (CBC) and serum vitamin B12; if CBC shows macrocytosis or clinical concern persists despite normal/low‑normal B12, proceed to serum methylmalonic acid (MMA).

Use MMA as a second-line/metabolic marker when serum B12 is equivocal or clinical suspicion remains.
Document CBC findings (e.g., macrocytosis) and the rationale for progressing to MMA.

Step Therapy

Testing sequence — initial serum B12 + CBC, then serum MMA for equivocal or suspicious cases

Order initial serum B12 together with a CBC; if serum B12 is low or low-normal or clinical suspicion persists, order serum MMA as the next-line test to confirm metabolic deficiency.

If MMA is unavailable, consider total homocysteine as an alternative where appropriate (note: homocysteine is not covered for confirmation per policy).
Record prior CBC/B12 results and the specific clinical concern when requesting MMA.

Note

Frequency-related sequencing note — three-month testing frequency added (Dec 2024)

The policy revision dated 12/04/2024 added a three-month testing frequency for vitamin B testing, establishing that total vitamin B12 testing meets coverage criteria once every three months for specified situations.

Operational ordering and repeat-testing expectations should reflect the added once-every-3-months rule for covered indications.

Documentation Required

Required clinical documentation — CBC and serum B12 required; MMA when B12 is equivocal

Document a complete blood count and serum vitamin B12 when evaluating suspected deficiency; if serum B12 is normal or low‑normal but suspicion remains, document the rationale for and order serum methylmalonic acid (MMA).

Include clinical symptoms, relevant risk factors (e.g., bariatric surgery, metformin use), and prior CBC/B12 results in the order and medical record.
For monitoring treatment, document treatment status and objective markers used to assess response.

Documentation Required

Pre-treatment sampling and documentation — collect plasma/urine for metabolic testing prior to treatment

When high total homocysteine is present or metabolic testing is indicated, obtain plasma and urine samples for MMA, methionine, folate, and B12 before starting treatment and document the clinical rationale.

Ensure samples are collected prior to treatment initiation to preserve diagnostic accuracy.
Record the reason for pre-treatment sampling and any relevant biochemical abnormalities in the chart.

Billing Rule

Billing/documentation expectations — follow member EOC, state/federal rules, and coding guidance

Reimbursement decisions rely on the member's evidence of coverage, applicable state and federal requirements, and the provider's participation agreement; follow national coding/edit rules and AMA/CMS guidance when documenting claims.

Use appropriate coding modifiers and billing practices consistent with CMS/NCCI, and verify coverage prior to testing.
Maintain documentation supporting medical necessity in the medical record to substantiate claims.

Denial Risk

Denial triggers — asymptomatic screening and non-covered confirmatory tests

Total vitamin B12 testing for healthy, asymptomatic individuals is not covered; holotranscobalamin and homocysteine testing are not covered for confirmation of B12 deficiency and may be denied.

Do not order B12 testing as routine population screening in average‑risk asymptomatic patients; such orders risk denial.
Holotranscobalamin and homocysteine should not be used for confirmation per the policy's not-covered list.

Denial Risk

Screening asymptomatic patients — avoid routine screening without clinical indication

Do not screen asymptomatic persons at average risk for vitamin B12 deficiency; tests ordered without documented clinical indication or risk factors may be inconsistent with guideline-based practice and may be denied.

Ensure orders include documented symptoms or risk factors when testing is requested to support medical necessity.
Review guidelines (e.g., AAFP) which do not recommend average-risk screening before ordering tests.

Denial Risk

Coding and billing noncompliance — risk of denial or recoupment if rules not followed

Failure to follow proper coding, billing, and reimbursement policy guidelines (including national and payer-specific edits) could result in denial and/or recoupment of claim payments; verify coding and maintain supporting documentation.

Follow NCCI, NCD/LCD, AMA/CMS, and state‑specific coding rules when submitting claims.
Retain clinical documentation that justifies medical necessity in case of audit or claim review.

Billing Rule

ORDERING REQUIREMENTS — follow payer coding/billing rules and verify prior auth

Ensure orders and claims comply with payer-specific coding and billing rules; prior authorization and coverage determinations depend on the member's evidence of coverage and provider participation agreement.

Verify whether prior authorization is required for specific tests per the member's plan before performing non-urgent testing.
Follow Healthfirst and CMS coding principles when preparing claims.

Emerging marker of impaired B12 status and potential first‑line test per some guidance

Availability/validationNot yet clinically validated or widely available for routine use

inv-28: MMA described as metabolic biomarker that increases in true functional B12 deficiency and helps clarify biochemical/functional deficiency when serum B12 is equivocal

RoleMMA is a metabolic biomarker that increases in true functional B12 deficiency and helps clarify biochemical/functional deficiency when serum B12 is equivocal

Diagnostic useUseful as a second‑line test when serum B12 is normal or low‑normal but clinical suspicion persists

Guideline supportRecommended by consensus groups and hematology guidelines to guide diagnosis and monitor treatment effectiveness

inv-29: Holotranscobalamin — The metabolically active fraction of vitamin B12; emerging test but limited availability and validation

DefinitionHolotranscobalamin is the metabolically active fraction of vitamin B12

Emerging roleMay perform better than serum cobalamin as an indicator of B12 status due to representing biologically active fraction

LimitationsLimited availability, clinical validation, and indeterminate specificity currently restrict widespread use

inv-30: Initial test options — NICE recommends either total B12 (serum cobalamin) or active B12 (holotranscobalamin) as the initial test for suspected B12 deficiency

Initial test optionsEither total B12 (serum cobalamin) or active B12 (holotranscobalamin) can be used as the initial test for suspected B12 deficiency per NICE guidance

ExceptionsNICE notes exceptions (e.g., pregnancy or suspected nitrous‑oxide related deficiency) where testing choice may differ

Practical noteAAFP recommends starting with CBC and serum B12; use MMA if B12 is normal/low‑normal but suspicion remains

inv-31: Biomarker limitations — BMJ notes that serum B12, homocysteine, and MMA are unreliable predictors of B12-responsive neuropathy and that biomarkers can normalize post-treatment

LimitationSerum B12, homocysteine, and MMA are unreliable predictors of B12‑responsive neuropathy per BMJ

Monitoring implicationBiomarkers may normalize faster than clinical improvement; monitor symptoms (e.g., every 2–3 months) rather than relying solely on biomarkers

Diagnostic cautionNo single test reliably diagnoses or refutes B12 deficiency; interpret biomarkers alongside clinical findings