MBS Review

Folate Testing

Protocol

July 2013

This protocol was commissioned by the Department of Health and Ageing

Prepared by HealthConsult Pty Ltd (ACN 118 337 821) for the Department of Health and Ageing

Project Team:Joe Scuteri HealthConsult Project DirectorLisa Fodero HealthConsult Project ManagerDiah Elhassen HealthConsult Research Analyst

HealthConsult Pty LtdHead Office: 4409/93 Liverpool Street, Sydney, New South Wales, 2000Phone (02) 9261 3707: Fax (02) 9261 3705: Email: admin@healthconsult.com.au

CONTENTS

ABBREVIATIONS.................................................................................................................1

INTRODUCTION TO MBS REVIEWS..............................................................................2

Principles to Guide MBS Reviews...........................................................................................3

Objectives of the Review.........................................................................................................3

Purpose of the Protocol...........................................................................................................3

Stakeholder Consultations.......................................................................................................3

Public Consultations................................................................................................................4

Medical Craft Groups / Key Stakeholders................................................................................4

BACKGROUND.....................................................................................................................5

Functions of folate in the human body.....................................................................................5

Causes of folate deficiencies...................................................................................................6

Diseases caused by folate deficiencies...................................................................................7

Folate testing.........................................................................................................................8

Prevalence of folate deficiencies in Australia..................................................................9

Clinical Flow Chart.................................................................................................................10

METHODOLOGY...............................................................................................................11

Population, Intervention, Comparator, Outcomes (PICO)...........................................11

MBS data.............................................................................................................................13

Guideline concordance......................................................................................................13

Economic evaluation......................................................................................................... 13

REFERENCES.....................................................................................................................14

APPENDIX A – MBS DATA...............................................................................................16

APPENDIX B - SEARCH TERM STRATEGY................................................................20

APPENDIX C – SEARCH STRATEGY............................................................................28

ABBREVIATIONS

µg MicrogramAD Alzheimer’s DiseaseAIHW Australian Institute of Health and WelfareANZFSC Australia and New Zealand Food Standards CodeCMFM Comprehensive Management Framework for the MBSCoA Coenzyme ACVD Cardiovascular diseaseDepartment Department of Health and Ageing

DNA Deoxyribonucleic acidESC Evaluation Sub-Committee (of MSAC)FDA Food and Drug AdministrationHPLC High performance liquid chromatographyholoTC Holotranscobalamin IIIF Intrinsic factorMSAC Medical Services Advisory CommitteeMBS Medicare Benefits ScheduleMMA Methylmalonic acidng/ml Nanogram per millilitreNTD Neural Tube Defectsoz OuncePA Pernicious anaemiaPASC Protocol Advisory Sub-CommitteePBS Pharmaceutical Benefits Schemepg/ml Picogram per millilitrePICO Population, intervention, comparator, outcomePmol/L Picomole per LitreRCC Review Consultation CommitteeRBC Red Blood CellRDA Recommended Dietary AllowanceTGA Therapeutic Goods Administration

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INTRODUCTION TO MBS REVIEWS

In the 2011-12 Budget, the Australian Government committed to continue the systematic review of Medicare Benefits Schedule (MBS) items to ensure that they reflect contemporary evidence, improve health outcomes for patients and represent value for money under the Comprehensive Management Framework for the MBS (CMFM).

Reviews support the public funding of evidence-based, cost-effective clinical practice through the MBS.

The MBS Reviews process includes the consideration of policy issues related to services funded under the MBS and is designed to have flexibility depending on the complexity of the issues pertaining to the particular review. For example, where there is a single MBS item or service the review may be focussed and timeframes may not be as exhaustive as a review that include multiple MBS items with related policy issues or non MBS issues. Non MBS issues that require a different process (such as pharmaceuticals or prostheses), and policy issues that are not appropriately dealt with by the Medical Services Advisory Committee (MSAC) process will be identified and addressed in separate processes which will inform the review.

The first stage of a review is the identification of the scope. Reviews with single MBS services/issues will follow the MBS pathway and will be considered by MSAC using the MSAC process. For reviews with multiple MBS services or a specialty and policy issues, the scope and pathway (MBS pathway and policy pathway) will be confirmed by the Review Consultation Committee (RCC), a time limited committee of nominated experts, determined and chaired by the Department.

The MBS pathway will follow the MSAC process and include the: development of a protocol; collection and evaluation of evidence; and advice and recommendations to the Minister through the Department.

The pathway for policy and other issues depends on the issues identified in the scope. There will be interactions between the MBS and policy pathways and stakeholders will be consulted throughout the review process; ensuring alignment of processes and consistency in deliberations.

The engagement with stakeholders is a critical component of the reviews process and issues will be dealt with in a consultative fashion. The role of the RCC is to advise the Department on policy issues and the MSAC and its subcommittees is advising on MBS matters. The review process is flexible, ensuring that new and emerging issues and feedback from the RCC, MSAC or public consultations can be incorporated into the reports.

The advice and recommendations provided by the RCC and MSAC to the Department informs the advice for the Minister.

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Principles to Guide MBS ReviewsReviews will:

have a primary focus on improving health outcomes and the financial sustainability of the MBS, through consideration of areas potentially representing:

patient safety risk; limited health benefit; and/or inappropriate use (under or over use)

be evidence-based and fit-for-purpose; be conducted in consultation with key stakeholders including, but not limited to, the

medical profession and consumers; include opportunities for public submission; be published; and use Government resources efficiently.

Objectives of the ReviewTo ensure the clinical and financial sustainability of the MBS, reviews will assess specific services or MBS item(s) and associated policy issues in a focused, fit-for-purpose, evidence based process. Findings will recognise that MBS funding should align with contemporary evidence, reflecting appropriate patient groups and best clinical practice.

Purpose of the Protocol This document outlines the methodology for providing evidence based analysis to support the review of services for folate testing, specifically the frequency of testing and the appropriate patient population for testing. The Protocol outlines the review methodology, clinical research questions the review will focus on, methods to identify and appraise the evidence and key stakeholder groups and experts to be consulted during the conduct of the review.

Stakeholder Consultations The Department is responsible for the review process including documents developed for policy and MBS issues and contractual arrangements for the development of the protocol and other report documents for the review. This includes ensuring that the relevant documents are available online for public consultation at the appropriate time and that comments are incorporated into informing the review process.

The Department’s management of stakeholder engagement and negotiations with the relevant medical craft groups and key stakeholders will ensure the review findings are informed by consultations.

Following the finalisation of the review process, the advice to the Minister for Health on the findings of the review will be informed by the review reports, advice and recommendations from MSAC and RCC, public consultations and also other information that is relevant to the review including budgetary considerations.

Questions to be directed to the RCC will include, but are not limited to:(1) Is folate testing appropriate for MBS reimbursement?

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(2) What are the expected patient health outcomes with regard to patient groups, type of intervention and practitioners ordering and performing (accreditation and training) the folate testing?

(3) What are the clinical indications for medically necessary folate testing? (4) Are current assays used for the detection of folate levels accurate? Do these the true status

of folate in the Australian population? (5) What effect does testing have on treatment?

Public Consultations The invitations to the general public (which include all stakeholders - patients, consumer groups, individual service providers, health professionals and manufacturers) to provide comment on the draft documents during the review process are critical to the review process. The documents will be available on the MSAC website (www.msac.gov.au) inviting the public to submit written comments over a four week period. The purpose of the feedback is to inform the final reports and recommendations to the Minister.

Medical Craft Groups / Key StakeholdersThe following clinical craft groups and key stakeholders have been identified as having an interest in this review: Osteoporosis Australia; IVD Australia; Australia and New Zealand Bone and Mineral Society; Endocrine Society of Australia; National Prescribing Network; Australian Association of Pathology Practices; Australian Medical Association; Consumers Health Forum of Australia; National Coalition of Public Pathology; Royal Australian College of General Practitioners; and Royal College of Pathologists of Australasia.

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BACKGROUND

Mechanism of folate absorptionFolate is a water soluble B vitamin (also known as vitamin B9) that occurs naturally in food. Dietary folate is absorbed in the jejunum (i.e. the middle section of the small intestine).(1) Folate is also absorbed in the colon, and it is suggested that colonic absorption may contribute significantly to total folate absorption.(2) Absorbed folate is transported to the liver, which contains about half the bodies pool of folate (3), while the rest is transported via the systemic circulation to body tissues.

Functions of folate in the human bodyIn humans, vitamin B12 and folate are linked by two enzymatic reactions where they function as cofactors (i.e. a cofactor is a component, other than the protein portion, of many enzymes to facilitate the catalytic activity of the enzyme)(4). Vitamin B12 is required as a cofactor in both reactions, whereas folate is required in only one of the reactions (see Figure 2).(5)

Figure 2: The enzymatic reactions that require vitamin B12 and folate (folic acid) as cofactors (6)

In the first reaction, vitamin B12 is required for the conversion of methylmalonic acid (MMA) to succinyl-CoA. MMA is a substance produced when proteins in the body are broken down.(6) Folate does not play any role in this reaction. Deficiency in vitamin B12 can lead to increased levels of serum MMA.(5)

In the second reaction, both vitamin B12 (in the form of methylcobalamin) and folic acid act as cofactors in the conversion of the substrate homocysteine (a homologue of the amino acids cysteine and methionine) to methionine (an amino acid and one of the 20 building blocks of proteins) by the enzyme methionine synthase.(5, 8) More importantly, this pathway is closely linked to the generation of thymidine which is vital for deoxyribonucleic acid (DNA, i.e. the building block of the human body which carries genetic information) synthesis. A deficiency in either vitamin B12 or folic acid or both can lead to increased homocysteine levels in plasma.(5) In addition, deficiency of either vitamins can result in perturbation of these two key pathways with consequent disruption of DNA synthesis caused by thymidine lack and resulting in megaloblastic anaemia, as well as other adverse effects on the nervous system and other organs.(5) It is this metabolic reaction that clearly links the two vitamins and is

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responsible for the common or shared neuropsychiatric and haematologic disorders discussed in the following sections.

Folate: dietary sources, fortification, and supplementsFolate is naturally present in a variety of foods including leafy green vegetables, fruits and dried beans and peas. Examples of some of the dietary food sources and their folate content are also shown in Table 1. The recommended dietary allowance (RDA) for folate for adults is 400µg/day (9).

Table 1: Examples of dietary sources of folate (9, 10)

Type of food Estimated folate content (micrograms µg)

Lentils (1/2 cup cooked) 179Spinach (1/2 cup cooked) 115Tomato juice (1 cup) 49Orange juice (1 cup) 47Green peas (1/2 cup cooked) 47Strawberries 40Baked beans (1 cup) 30Banana (1 medium) 24

Food fortification is defined as the process of adding micronutrients (such as vitamins and minerals) to food as permitted by the Australian and New Zealand Food Standards Code (ANZFSC).(11) Regulations regarding the fortification of foods with folate vary between countries. The voluntary addition of folic acid to certain foods has been permitted in Australia since 1996.(12) Since then a variety of products have been fortified with folic acid. However, the mandatory fortification of folate in Australia was initiated in September 2009 under Clause 4 (2) of Standard 2.1.1 of the ANZFSC. This ANZFSC states that folic acid (folic acid is the synthetic form of folate) (13) is added within the prescribed range of 200–300 μg per 100 grams of wheat flour used for bread making.(14) This level of folic acid fortification is expected to prevent between 14 and 49 neural tube defects (NTD) per year in Australia.(14) In the US, the Food and Drug Administration (FDA) mandated the addition of folic acid to breads, cereals, flours, corn meals, rice, pastas, and other grain products as they are widely consumed in the US.(15) As a result most diets in the US now provide recommended amounts of folate equivalents.(16)

The risk of toxicity from folic acid intake from supplements and/or fortified foods is low .(17) Folate is a water soluble vitamin, and therefore any excess intake is usually excreted in the urine.

Causes of folate deficienciesTable 2 describes causes of folate deficiencies which can be divided into four categories: nutritional deficiency, increased requirements, impaired absorption, and other gastrointestinal causes.(8, 18)

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Table 2: Causes of folate deficiencies

Nutritional deficiency

Increased requirements Impaired absorption

Other gastrointestinal

causes Poor intake of

meats and dairy products in the elderly population (aged 65 and above) (19)

Alcoholism (1, 20)

Strict vegan diets (19)

Malnutrition (28) and avoidance of fortified bread due to coeliac disease (29,

30)

Due to pregnancy and lactation (31)

Autoimmune disease with autoantibodies against the intrinsic factor (pernicious anaemia) (32) (33)

Atrophic body gastritis (due to autoantibodies to gastric parietal cells)(34)

Gastrectomy (35)

Prolonged use of acid-suppression therapy or drugs (36)

Chronic gastrointestinal symptoms e.g. dyspepsia, recurrent peptic ulcer, diarrhoea (5)

Coeliac disease (37)

Crohn’s disease (38)

Patients with intestinal surgery gastric resection, sleeve or banding surgery) (39)

Tapeworms and other intestinal parasites (35)

Ileocystoplasty (i.e. a surgical reconstruction of the bladder involving the use of an isolated segment of ileum to augment bladder capacity) (40)

In general, folate deficiency is most often the result of decreased intake and is more common in developing and socioeconomically distressed countries. Folate deficiency as a result of decreased intake is very rare now following mandatory fortification of folate in 2009. It can still occur when there is a decreased absorption due to gastrointestinal problems or an increased folate requirement arising due to pregnancy, lactation, and prematurity. Other conditions associated with increased cell turnover such as leukaemia’s, aggressive lymphomas, and other tumours associated with a high proliferative rate can also cause increased folate demand.(33)

Diseases caused by folate deficienciesThe main function of folate is to help form red blood cells (RBCs) and produce DNA. Folate deficiency also contributes to many neurological and psychological disorders including dementia, impaired cognition, depression, psychosis, and Alzheimer’s disease.(47, 48) Folate deficiency is also associated with raised serum homocysteine levels. It remains unclear whether elevated serum homocysteine levels increases the risk of developing cardiovascular disease (CVD). There are few studies that reported that increased serum levels of homocysteine are associated with increased risk of CVD.(49, 50) However, a recent systematic review and meta-analysis of 26 RCTs on the efficacy of folic acid supplementation showed that it did not significantly change in the risk of CVD.(51) Folate also prevents neural tube defects during fetal development.(52) The full range of mechanisms by which deficiencies in folate may contribute to these neurologic disorders is unclear. However, one likely major impact of folate deprivation is increased levels of homocysteine, since folate is a necessary

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cofactor for the enzyme that mediates the conversion of homocysteine to methionine (see Figure 2).

Table 3: Clinical manifestations of folate deficienciesHaematologic (5) Neurologic(21) Psychiatric(41) Cardiovascular (37, 38)

Megaloblastic anaemia

Panycytopenia (Leukopenia, thrombocytopenia)

Pernicious anaemia (i.e. large immature RBCs)

Paresthesias (i.e. a skin sensation such as burning or itching with no apparent physical cause)

Peripheral neuropathy

Combined systems disease (demyelination of peripheral nerves, spinal cord, cranial nerves and the brain)

Irritability, personality change

Mild memory impairment, dementia

depression psychosis Alzheimer’s

Disease(32)

Possible increased risk of myocardial infarction and stroke

Folate testingTests commonly used for the detection of folate are:(18)

serum folate: Serum folate depends on recent dietary intake, therefore this test does not reflect on the long-term folate status in the body. The normal reference range for serum folate is 7-45 nmol/L (3-20 ng/ml) (42).

red blood cell folate: this test measures the amount of folate in RBCs and is reflective of the long-term folate status in the body (i.e. stores in the liver).(43) However, this test is more complex to perform than the serum folate assay and requires more steps in sample handling before analysis, which may be one of the reasons why the precision of the red cell folate assay is much less than that of the serum folate assay.(44) In addition, red cell folate concentrations are often low in patients with B12 deficiency(43) and are inversely associated with haemoglobin concentrations.(45) The reference interval for red cell folate is highly method dependent, and an approximate normal range for red cell folate is 317-1422 nmol/L RBC (140-602 ng/ml RBC) (42). Levels less than 140 ng/ml are indicative of folate deficiency.

plasma homocysteine: As shown in Figure 2, vitamin B12 and folate are required for the conversion of homocysteine to methionine at the cellular level. Therefore it is considered as a functional indicator of vitamin B12 or folate adequacy. Special care (and collection tubes) should be taken when collecting blood samples for testing using this method as homocysteine concentration can rise after blood collection in certain tubes due to ongoing release of homocysteine by the RBCs in vitro.(46) Inadequate fasting or a high protein meal the night before the blood test can also falsely increase the plasma homocysteine levels.

There is a lack of strong evidence in the literature to support the clinical practice that folate deficiency in an individual is determined by performing the serum folate as well as the RBC folate measurements. The evidence that suggests that red cell folate is considered a better indicator of folate status than serum folate is old(47). A more recent study that analysed the use of the two methodologies in determining folate deficiency in individuals reported that serum folate measurements provide equivalent information to RBC folate measurements.(48)

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The alternative approach for assessment of folate status involves measurement of the plasma homocysteine, which is known to increase in folate deficiency and provides certain advantages over direct measurement of serum folate concentrations.(8, 38) However, homocysteine requires folate as a cofactor for its conversion to methionine (refer to Figure 2). Consequently, plasma homocysteine concentrations rise in folate deficiencies. Therefore, the only way to distinguish whether an individual is deficient in folate is to measure serum MMA. Increased serum levels of MMA are solely attributed to vitamin B12 deficiency. It is important to note that the correction of folate deficiency through the use of supplementation and/or fortification may mask an occult vitamin B12 deficiency and further exacerbate or initiate neurologic disease. Therefore it is recommended that clinicians consider ruling out vitamin B12 deficiency before initiating folic acid therapy.(49)

Serum folate target valuesThe cut-off value for folate deficiency varies markedly between laboratories worldwide. Table 4 presents the “usual or approximate” reference intervals for folate deficiencies.

Table 4: Folate (42) reference intervals

Status Folate (ng/ml)‡ RBC folate (ng/ml RBC)Normal range 3-20 140-628

deficient < 3 (7 nmol/L) < 140 (305 nmole/L)

Prevalence of folate deficiencies in AustraliaThe prevalence of folic acid deficiency in the general Australian population is also unknown. A report published by AIHW in 2011 (50) found that the mean folic acid intake for women aged 16–44 years (the target population) in Australia (and before the introduction of the mandatory folic acid fortification program) was 108 μg/day, which is well below the recommended 400 μg/day. In addition, there were 149 pregnancies affected by NTDs in 2005 in Australia (rate of 13.3 per 10,000 births) in the three states that provide the most accurate baseline of NTD incidence (South Australia, Western Australia and Victoria).(50)

A retrospective study was conducted between April 2007 and April 2010 to determine the impact of the mandatory folic acid fortification program on the blood folate levels of an Australian population since its introduction in 2009.(51) This study reported that the prevalence of low serum folate levels decreased by 77% in all samples tested (the samples constituted 20,592 blood samples collected from a wide variety of patients and analysed in a public hospital diagnostic pathology laboratory). The prevalence of low RBC folate levels also decreased by 85%. The prevalence of low RBC folate levels for females of childbearing age was 0.16% of all samples. However, there was no statistics on the incidence of NTDs in newborn babies. The authors of this study concluded that the introduction of the mandatory fortification with folic acid has significantly reduced the prevalence of folate deficiency in Australia, and more importantly in women of childbearing age.

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Clinical Flow ChartThe clinical decision pathway which determines whether folate testing should be undertaken is provided in Figures 3.

Figure 3: Clinical flow chart for folate testing

Patient presents to clinician (e.g. General Practitioner, Obstetrician etc)

Does the patient have any of the following clinical symptoms of folate deficiency?

Neuropsychiatric symptoms (mild) including: • dementia; and/or• depression; and/or• psychosis, and/or• personality changes.

• anaemia; and/or• macrocytosis.

Does the patient have any of the following haematological symptoms of folate deficiency?

• patients with coeliac disease; and/or • pregnancy; and/or • dietary deficiency; and/or • alcoholism; and/or • malignancy (e.g. leukaemia).

Does the patient have any of the following risk factors associated with folate deficiency?

Measure Vitamin B12 and/or folate and claim

MBS item 66602 or 66599

Patient ineligible to claim benefits under MBS item numbers 66599 or 66602

Is Vitamin B12/folate testing medically

necessary?

Yes Yes

No

No

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METHODOLOGY

The main methodology for the review will be mini-health technology assessments:

a comprehensive systematic search of the scientific literature will be conducted to identify relevant studies addressing the key clinical/research questions.

To translate the evidence into the Australian context, the review will consider:

Secondary data analysis:o MBS and National Hospital Morbidity data will be analysed to examine the existing

population utilisation of services and assess whether existing MBS item numbers for the services are appropriate.

Guideline concordance:o an analysis of the MBS services will be assessed relative to ‘best practice’ as

recommended in relevant Clinical Practice Guidelines and relevant practice in Australia.

Stakeholder consultation:o clinician engagement (e.g. CRC, MESP and submission authors) to understand

existing services and practices in Australia; ando consumer engagement to determine consumer experiences with the services under

review. Economic evaluation

o preliminary economic evaluation will be conducted as part of the review, relying on studies identified through the systematic literature review.

The above information will take on additional significance when there is a lack of clear, high quality evidence.

Population, Intervention, Comparator, Outcomes (PICO)The PICO (Population, Intervention, Comparator, Outcomes) criteria (54) are used to develop well-defined questions for each review. This involves focusing the question on the following four elements: the target population for the intervention; the intervention being considered; the comparator for the existing MBS service (where relevant); and the clinical outcomes that are most relevant to assess safety and effectiveness.

The PICO criteria have been determined on the basis of information provided in the literature, as well as clinical advice. These criteria will be applied when selecting literature for these mini-HTAs. Additional criteria for selecting literature have also been outlined (i.e. relevant study designs for assessing the safety and effectiveness of the service, time period within which the literature will be sourced, and language restrictions as discussed above and in appendix C). The PICO for the review of vitamin folate testing are shown in Table 5.

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Table 5: Clinical research questions for the folate testing Population Intervention Comparator Outcomes(1) General Health population

(includes pregnant women, elderly, alcoholics, vegetarians)

Folate testing Supplementation

Safety Complications associated with

the procedure (e.g. infection, needle injuries)

Effectiveness Physical health outcomes as a

consequence of the procedure (e.g. all-cause mortality, anaemia, NTDs, CVD, neuropathy, depression and dementia).

(2) Infants with metabolic disease

(3) Patients with anaemia and haematologic diseases

(4) Patients with neurologic disease

(5) Patients with gastrointestinal and malabsorption disorders

(6) Patients with psychiatric disorders

Literature review

A comprehensive search of the scientific literature will be conducted to identify relevant studies addressing the key questions. The databases to be included in the search are: MEDLINE® (from 1966 to present), MEDLINE® In-Process & Other Non-Indexed Citations, EMBASE (Excerpta Medica published by Elsevier), the Cumulative Index to Nursing & Allied Health Literature (CINAHL) and Cochrane databases. The search will be restricted to English language studies of humans. In electronic searches we will use various terms for, limited to humans, and relevant research designs as shown in Appendix 1.

Reference lists of related systematic reviews and selected narrative reviews and primary articles should be reviewed. Databases maintained by health technology assessment (HTA) agencies should be reviewed to identify existing assessments of folate testing.

In terms of supplementary search strategies, as part of consultations with pathologists and general practitioners, they should be asked if they are aware of any clinical guidelines, unpublished studies, or reviews relevant to the review of folate testing.

Noting that vitamin B12 and folate tests are claimed under the same MBS items, the research questions to be addressed as part of the review protocol using the literature review include,:(1) What are the appropriate clinical indications for medically necessary folate testing?(2) What is the strength of evidence for the effectiveness of folate testing in improving

outcomes in each target population (e.g. children, pregnant women, elderly, vegetarians, and patients with hematologic and neurologic disorders) across the patient journey?

(3) What are the safety and quality implications (including morbidity, mortality and patient satisfaction) associated with folate testing in each target population? How do safety and quality outcomes of folate testing vary according to:a. the difference in testing methodologies?b. frequency of testing?

(4) What is the evidence regarding the cost implications associated with vitamin B12/folate testing services in each target population across the patient journey?

(5) What is the evidence regarding the cost implications associated with vitamin B12/folate testing in each target population compared with not testing?

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MBS dataMBS data are available for MBS item numbers 66599 and 66602 since the early 1990s. A brief review of the available MBS data for the purposes of drafting the review protocol identified an overall increase in claims for vitamin B12/folate testing.

The clinical/research questions to be addressed as part of the review using MBS data include:a. How frequent are claims for the MBS item numbers under review (66599 and 66602)?b. Are there any age, sex, temporal or geographic trends associated with usage of these

item numbers?c. What are the characteristics of patients undergoing vitamin B12/folate testing?d. Are the Medicare claims data consistent with trends in the incidence/prevalence of the

conditions/diseases being addressed by the services?e. What is the prescriber profile of benefits claimed for vitamin B12/folate testing? f. Are there other pathology tests claimed in association with vitamin B12/folate testing?

Guideline concordanceAn analysis of the two MBS item numbers, 66599 and 66602 will be assessed relative to ‘best practice’ as recommended in relevant clinical practice guidelines and relevant practice in Australia. Where formalised clinical practice guidelines do not exist, the review should take account of other guidelines in operation in comparable health systems overseas. Differences in the purpose and intended audience of any such guidelines should be considered, documented and acknowledged in the process of undertaking the review.

The clinical/research questions to be addressed as part of the review using guideline concordance include:(1) Is the descriptor for MBS items, 66599 and 66602 consistent with evidence-based (or in

the absence of evidence, consensus-based) recommendations provided in relevant clinical practice guidelines?

Economic evaluationOnly a preliminary economic evaluation will be conducted as part of conducting the review, relying on studies identified through the systematic literature review. In the literature searches, acceptable evidence would include trial-based costing studies, cost analyses and economic modelling studies. Acceptable outcomes would include: cost, incremental cost-effectiveness ratio e.g. cost per event avoided, cost per life year gained, cost per quality adjusted life year or disability adjusted life year. The applicability of any identified economic analyses to the Australian health system will be assessed.

The clinical/research questions to be addressed as part of the review using the economic evaluation component include:(1) What is the evidence regarding the cost implications associated with folate testing in each

target population across the patient journey?(2) Is the current fee structure for the items appropriate?

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27. Kaushansky K BE, Seligsohn U, Lichtman MA, Kipps TJ, Prchal JT,. Folate, cobalamin, and megaloblastic anemias. 8th ed ed. R. G, editor. New York: McGraw-Hill; 2010.

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28. Sipponen P, Laxen F, Huotari K, Harkonen M. Prevalence of low vitamin B12 and high homocysteine in serum in an elderly male population: association with atrophic gastritis and Helicobacter pylori infection. Scand J Gastroenterol. 2003 Dec;38(12):1209-16.

29. Green R MJ. Handbook of Vitamins. 4th ed. Zempleni J RR, editor. Boca Raton, FL: Taylor & Francis Group; 2007.

30. Schubert ML. Gastric secretion. Curr Opin Gastroenterol. 2007 Nov;23(6):595-601.31. Ponziani FR, Cazzato IA, Danese S, Fagiuoli S, Gionchetti P, Annicchiarico BE, et al. Folate in

gastrointestinal health and disease. Eur Rev Med Pharmacol Sci. 2012 Mar;16(3):376-85.32. Yakut M, Ustun Y, Kabacam G, Soykan I. Serum vitamin B12 and folate status in patients with

inflammatory bowel diseases. Eur J Intern Med. 2010 Aug;21(4):320-3.33. Aarts EO, Janssen IM, Berends FJ. The gastric sleeve: losing weight as fast as micronutrients? Obes

Surg. 2011 Feb;21(2):207-11.34. Vanderbrink BA, Cain MP, King S, Meldrum K, Kaefer M, Misseri R, et al. Is oral vitamin B(12)

therapy effective for vitamin B(12) deficiency in patients with prior ileocystoplasty? J Urol. 2010 Oct;184(4 Suppl):1781-5.

35. Ramos MI, Allen LH, Mungas DM, Jagust WJ, Haan MN, Green R, et al. Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging. Am J Clin Nutr. 2005 Dec;82(6):1346-52.

36. Wang HX, Wahlin A, Basun H, Fastbom J, Winblad B, Fratiglioni L. Vitamin B(12) and folate in relation to the development of Alzheimer's disease. Neurology. 2001 May 8;56(9):1188-94.

37. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. The New England journal of medicine. 1997 Jul 24;337(4):230-6.

38. Carmel R, Green R, Rosenblatt DS, Watkins D. Update on cobalamin, folate, and homocysteine. Hematology / the Education Program of the American Society of Hematology American Society of Hematology Education Program. 2003:62-81.

39. Yang HT, Lee M, Hong KS, Ovbiagele B, Saver JL. Efficacy of folic acid supplementation in cardiovascular disease prevention: an updated meta-analysis of randomized controlled trials. Eur J Intern Med. 2012 Dec;23(8):745-54.

40. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet. 1991 Jul 20;338(8760):131-7.

41. Lindenbaum J, Healton EB, Savage DG, Brust JC, Garrett TJ, Podell ER, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. The New England journal of medicine. 1988 Jun 30;318(26):1720-8.

42. Cook S-HDaJD. Laboratory reference range values. 2005.43. Guidelines on the investigation and diagnosis of cobalamin and folate deficiencies. A publication of the

British Committee for Standards in Haematology. BCSH General Haematology Test Force. Clin Lab Haematol. 1994 Jun;16(2):101-15.

44. NEQAS U. Haematinic assays scheme. Annual report 2001 Sutton, Coldfield2002.45. Arsenault JE, Mora-Plazas M, Forero Y, Lopez-Arana S, Baylin A, Villamor E. Hemoglobin

concentration is inversely associated with erythrocyte folate concentrations in Colombian school-age children, especially among children with low vitamin B12 status. Eur J Clin Nutr. 2009 Jul;63(7):842-9.

46. Louey W LZ, and Sikaris KA. Which Blood Collection Tube is Better for Homocysteine.47. Hoffbrand AV, Newcombe FA, Mollin DL. Method of assay of red cell folate activity and the value of

the assay as a test for folate deficiency. J Clin Pathol. 1966 Jan;19(1):17-28.48. Galloway M, Rushworth L. Red cell or serum folate? Results from the National Pathology Alliance

benchmarking review. J Clin Pathol. 2003 Dec;56(12):924-6.49. Tucker KL, Mahnken B, Wilson PW, Jacques P, Selhub J. Folic acid fortification of the food supply.

Potential benefits and risks for the elderly population. Jama. 1996 Dec 18;276(23):1879-85.50. AIHW. Mandatory folic acid and iodine fortification in Australia and New Zealand. Baseline report for

monitoringCanberra, ACT2011.51. Brown RD, Langshaw MR, Uhr EJ, Gibson JN, Joshua DE. The impact of mandatory fortification of

flour with folic acid on the blood folate levels of an Australian population. Med J Aust. 2011 Jan 17;194(2):65-7.

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53. NHMRC. NHMRC levels of evidence and grades for recommendations for developers of guidelines. [Internet]. Canberra, ACT: National Health and Medical Research Council; 2009. Available from: http://www.nhmrc.gov.au/_files_nhmrc/file/guidelines/evidence_statement_form.pdf.

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54. Richardson WS, Wilson MC, Nishikawa J, Hayward RS. The well-built clinical question: a key to evidence-based decisions. ACP J Club. 1995 Nov-Dec;123(3):A12-3.

APPENDIX A – MBS DATA

The MBS item numbers relevant to folate testingTable A.1 shows that there are currently two MBS item number for folate testing. Both of the items are subject to Rule 21 (i.e. no more than three of any combination of these tests are eligible for Medicare subsidy per patient per year).

Table A.1: Description of vitamin B12/folate testing funded under the MBS

Item Number MBS Item Number description66599 Serum B12 or red cell folate and, if required, serum folate

Schedule Fee: $23.75 Benefit: 75% = $17.85 85% = $20.2066602 Serum B12 and red cell folate and, if required, serum folate

Schedule Fee: $43.25 Benefit: 75%=$32.45 85%=$36.80Both of the items are subject to Rule 21: No more than three of any combination of these tests are eligible for Medicare subsidy per patient per year.Source: Department of Human Services

Year of adoption in health systemTable A.2 shows when the in-scope MBS item numbers were included on the MBS.

Table A.2: Item, description and schedule fee start dates for MBS item numbers

MBS Item number Type of date Date66599 Item Start Date 01-Nov-1998

Description Start Date 01-Mar-199966602 Item Start Date 01 Nov 1998

Description Start Date 01 Mar 1999Source: Department of Human Services

MBS utilisation and expenditureUtilisation of both in-scope MBS item numbers for vitamin B12/folate testing has increased substantially with services for item 66599 increasing by 106% and item 66602 increasing by 746% from 2000/01 to 2011/12 (Table A.3). In the financial year 2011/12, more than 2.3 million services were claimed for these two items.

Table A.3: Number of claims for vitamin B12/folate testing MBS items since 2000/2001

MBS item noFinancial year

08/09 09/10 10/11 11/12 12/1366599 382,241 399,282 447,211 520,68866602 1,476,465 1,586,968 1,667,155 1,821,490Total 1,858,706 1,986,250 2,114,366 2,342,178

Source: Department of Human Services

The pattern of use for item numbers 66599 and 66602 is further analysed in Figures A.1 and A.2 showing different patterns of usage by age, gender and time period. This analysis shows that vitamin B12/folate testing claimed under MBS item numbers 66599 and 66602 is

16

performed for both males and females and across all age groups. However, the number of claims for both items is approximately double for females than for males. Figure A.1 and Figure A.2 both show an increase from 2008 to 2012, almost doubling (green line) compared to 2004-2008 (red line) and 2000 to 2004 (blue line).

Figure A.1: Usage of MBS item 66599 by age and gender since 2000

17

Figure A.2: Usage of MBS item 66602 by age and gender since 2000

18

Figure A.3 shows the benefits paid for vitamin B12/folate testing MBS item numbers 66599 and 66602. The data show that there has been a significant increase in the benefits paid for both item numbers consistent with the increase in the volume of claims. Overall the total of benefits paid in 2011/12 for both items was $77.9m.

Figure A.3: Benefits paid for MBS item numbers 66599 and 66602 since 2000/01

00/01 01/02 02/03 03/04 04/05 05/06 06/07 07/08 08/09 09/10 10/11 11/120

10,000,000

20,000,000

30,000,000

40,000,000

50,000,000

60,000,000

70,000,000

80,000,000

66599 66602

Ben

efits

pai

d fo

r M

BS

item

nu

mbe

rs 6

599

and

666

02

Source: Department of Human Services Medicare

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APPENDIX B - SEARCH TERM STRATEGY

Clinical questions1. What is the safety and effectiveness of folate testing in patients undergoing the procedure

for functional conditions?

Table B.1: Search term strategy for clinical question one

Population Search Terms

1. General healthy population

Embase and MedlinePopulation – ((‘pregnancy’/exp OR ‘pregnancy’) OR (‘infant’/exp OR ‘infant’) OR (‘human milk’/exp OR ‘human milk’) OR (‘lactation’/exp OR ‘lactation’) OR (‘vegetarian’/exp OR ‘vegetarian’) OR (‘malnutrition’/exp OR ‘malnutrition’) OR (‘elderly’/exp OR ‘elderly’) OR (‘aged’/exp OR ‘aged’) OR (‘gluten free diet’/exp OR ‘gluten free diet’) OR (‘alcoholism’/exp OR ‘alcoholism’))ANDIntervention – (Vit*B12 OR ‘vitamin B12’/exp OR’ vitamin B12’ OR cobalamin OR cyanocobalamin OR hydroxycobalamin OR methylcobalamin OR ‘methymalonic acid /exp OR ‘methylmalonic acid’/exp OR ‘methylmalonic acid’ OR ‘MMA OR ‘methylmalonate’ OR ‘malonic acid’ OR ‘holotranscobalamin’/exp OR ‘holotranscobalamin’ OR ‘holoTC’/exp OR ‘holoTC’ OR ‘folate’/exp OR ‘folate’ OR ‘folic acid’/exp OR ‘folic acid’ OR ‘vitamin B9’/exp OR ‘vitamin B9’ OR ‘tetrahydrofolic acid’ OR ‘methylenetetrahydrofolic acid’ OR ‘serum folate’/exp OR ‘serum folate’ OR’ red cell folate’/exp OR ‘red cell folate’ OR ‘erythrocyte folate’/exp OR ‘erythrocyte folate’ OR ‘homocysteine’/exp OR ‘homocysteine’ OR ‘Hcy’) AND (‘testing’/exp OR ‘testing’ OR ‘haematologic test*’/exp OR ‘haematologic test*’)ANDLimits – [humans]/lim AND [english]/lim

CochranePopulation – ((MeSH descriptor Pregnancy explode all trees) OR (MeSH descriptor Infant explode all trees) OR (MeSH descriptor Human Milk explode all trees) OR (MeSH descriptor Lactation explode all trees) OR (MeSH descriptor vegetarian explode all trees) OR (MeSH descriptor Malnutrition explode all trees) OR (MeSH descriptor Aged explode all trees) OR (MeSH descriptor Alcoholism explode all trees) OR ((pregnancy) OR (pregnancy):ti,ab,kw) OR ((infant) OR (infant):ti,ab,kw) OR ((human milk) OR (human milk):ti,ab,kw) OR ((lactation) OR (lactation):ti,ab,kw) OR ((vegetarian) OR (vegetarian):ti,ab,kw) OR ((malnutrition) OR (malnutrition):ti,ab,kw) OR ((elderly) OR (eldrely):ti,ab,kw) OR ((aged) OR (aged):ti,ab,kw) OR ((gluten free diet) OR (gluten free diet):ti,ab,kw) OR ((alcoholism) OR (alcoholism):ti,ab,kw))ANDIntervention – ((MeSH descriptor Vitamin B12 explode all trees) OR (Vitamin B12):ti,ab,kw OR (MeSH descriptor Cobalamin explode all trees) OR (cobalamin):ti,ab,kw OR (MeSH descriptor Cyanocobalamin explode

20

Population Search Terms

all trees) OR (cyanocobalamin):ti,ab,kw OR (MeSH descriptor Hydroxycobalamin explode all trees) OR (hydroxycobalamin):ti,ab,kw OR (MeSH descriptor Methylcobalamin explode all trees) OR (methylcobalamin):ti,ab,kw OR (MeSH descriptor Methylmalonic acid explode all trees) OR (methylmalonic acid):ti,ab,kw OR (MeSH descriptor Methymalonate explode all trees) OR (methylmalonate):ti,ab,kw OR (MeSH descriptor Malonic acid explode all trees) OR (malonic acid):ti,ab,kw OR (MeSH descriptor Holotranscobalamin explode all trees) OR (holotranscobalamin):ti,ab,kw OR (MeSH descriptor HoloTC explode all trees) OR (holoTC):ti,ab,kw OR (MeSH descriptor Folate explode all trees) OR (folate):ti,ab,kw OR (MeSH descriptor Folic acid explode all trees) OR (folic acid):ti,ab,kw) ) OR (MeSH descriptor Vitamin B9 explode all trees) OR (vitamin B9):ti,ab,kw OR (MeSH descriptor Tetrahydrofolic acid explode all trees) OR (tetrahydrofolic acid):ti,ab,kw) ) OR (MeSH descriptor Methylenetetrahydrofolic acid explode all trees) OR (methylenetetrahydrofolic acid):ti,ab,kw OR (MeSH descriptor Serum folate explode all trees) OR (serum folate):ti,ab,kw) ) OR (MeSH descriptor Red cell folate explode all trees) OR (red cell folate):ti,ab,kw OR (MeSH descriptor Erythrocyte folate explode all trees) OR (erythrocyte folate):ti,ab,kw) ) OR (MeSH descriptor Homocysteine explode all trees) OR (homocysteine):ti,ab,kw ) AND ((MeSH descriptor Testing explode all trees) OR (Testing):ti,ab,kw OR (MeSH descriptor Haematologic test* explode al trees) OR (Haematologic test*):ti,ab,kw)ANDLimits [humans]/lim AND [english]/lim

2. Patients diagnosed with anaemia

Embase and MedlinePopulation – ((‘anaemia’/exp OR ‘anaemia’ OR ‘anemia’/exp OR ‘anemia’) OR (‘macrocyt*’/exp OR ‘macrocyt*)’ OR (‘megaloblastic ’/exp OR ‘megaloblastic’) OR (‘pernicious’/exp OR ‘pernicious’) OR (‘pancytopenia’/exp OR ‘pancytopenia’)) AND NOT (‘iron deficiency anaemia’/exp OR ‘iron deficiency anaemia’)ANDIntervention – (Vit*B12 OR ‘vitamin B12’/exp OR’ vitamin B12’ OR cobalamin OR cyanocobalamin OR hydroxycobalamin OR methylcobalamin OR ‘methymalonic acid /exp OR ‘methylmalonic acid’/exp OR ‘methylmalonic acid’ OR ‘MMA OR ‘methylmalonate’ OR ‘malonic acid’ OR ‘holotranscobalamin’/exp OR ‘holotranscobalamin’ OR ‘holoTC’/exp OR ‘holoTC’ OR ‘folate’/exp OR ‘folate’ OR ‘folic acid’/exp OR ‘folic acid’ OR ‘vitamin B9’/exp OR ‘vitamin B9’ OR ‘tetrahydrofolic acid’ OR ‘methylenetetrahydrofolic acid’ OR ‘serum folate’/exp OR ‘serum folate’ OR’ red cell folate’/exp OR ‘red cell folate’ OR ‘erythrocyte folate’/exp OR ‘erythrocyte folate’ OR ‘homocysteine’/exp OR ‘homocysteine’ OR ‘Hcy’) AND (‘testing’/exp OR ‘testing’ OR ‘haematologic test*’/exp OR ‘haematologic test*’)ANDLimits – [humans]/lim AND [english]/lim

CochranePopulation – ((MeSH descriptor Anaemia explode all trees) OR (MeSH descriptor Megaloblastic explode all trees) OR (MeSH descriptor

21

Population Search Terms

Pernicious explode all trees) OR (MeSH descriptor Pancytopenia explode all trees) OR ((anaemia) OR (anaemia):ti,ab,kw) OR ((megaloblastic) OR (megaloblastic):ti,ab,kw) OR (macrocyt*) OR ((pernicious) OR (pernicious):ti,ab,kw) OR ((pancytopenia) OR (pancytopenia):ti,ab,kw) ) AND NOT ((MeSH descriptor Iron deficiency anaemia) OR (iron deficiency anaemia):ti,ab,kw)ANDIntervention – ((MeSH descriptor Vitamin B12 explode all trees) OR (Vitamin B12):ti,ab,kw OR (MeSH descriptor Cobalamin explode all trees) OR (cobalamin):ti,ab,kw OR (MeSH descriptor Cyanocobalamin explode all trees) OR (cyanocobalamin):ti,ab,kw OR (MeSH descriptor Hydroxycobalamin explode all trees) OR (hydroxycobalamin):ti,ab,kw OR (MeSH descriptor Methylcobalamin explode all trees) OR (methylcobalamin):ti,ab,kw OR (MeSH descriptor Methylmalonic acid explode all trees) OR (methylmalonic acid):ti,ab,kw OR (MeSH descriptor Methymalonate explode all trees) OR (methylmalonate):ti,ab,kw OR (MeSH descriptor Malonic acid explode all trees) OR (malonic acid):ti,ab,kw OR (MeSH descriptor Holotranscobalamin explode all trees) OR (holotranscobalamin):ti,ab,kw OR (MeSH descriptor HoloTC explode all trees) OR (holoTC):ti,ab,kw OR (MeSH descriptor Folate explode all trees) OR (folate):ti,ab,kw OR (MeSH descriptor Folic acid explode all trees) OR (folic acid):ti,ab,kw) ) OR (MeSH descriptor Vitamin B9 explode all trees) OR (vitamin B9):ti,ab,kw OR (MeSH descriptor Tetrahydrofolic acid explode all trees) OR (tetrahydrofolic acid):ti,ab,kw) ) OR (MeSH descriptor Methylenetetrahydrofolic acid explode all trees) OR (methylenetetrahydrofolic acid):ti,ab,kw OR (MeSH descriptor Serum folate explode all trees) OR (serum folate):ti,ab,kw) ) OR (MeSH descriptor Red cell folate explode all trees) OR (red cell folate):ti,ab,kw OR (MeSH descriptor Erythrocyte folate explode all trees) OR (erythrocyte folate):ti,ab,kw) ) OR (MeSH descriptor Homocysteine explode all trees) OR (homocysteine):ti,ab,kw ) AND ((MeSH descriptor Testing explode all trees) OR (Testing):ti,ab,kw OR (MeSH descriptor Haematologic test* explode al trees) OR (Haematologic test*):ti,ab,kw)ANDLimits [humans]/lim AND [english]/lim

3. Patients with neurologic disease

Embase and MedlinePopulation – ((‘paresthesias’/exp OR ‘paresthesias’) OR (‘peripheral neuropathy’/exp OR ‘peripheral neuropathy’) OR (‘combined system disease’/exp OR ‘combined systems disease’))ANDIntervention – (Vit*B12 OR ‘vitamin B12’/exp OR’ vitamin B12’ OR cobalamin OR cyanocobalamin OR hydroxycobalamin OR methylcobalamin OR ‘methymalonic acid /exp OR ‘methylmalonic acid’/exp OR ‘methylmalonic acid’ OR ‘MMA OR ‘methylmalonate’ OR ‘malonic acid’ OR ‘holotranscobalamin’/exp OR ‘holotranscobalamin’ OR ‘holoTC’/exp OR ‘holoTC’ OR ‘folate’/exp OR ‘folate’ OR ‘folic acid’/exp OR ‘folic acid’ OR ‘vitamin B9’/exp OR ‘vitamin B9’ OR ‘tetrahydrofolic acid’ OR ‘methylenetetrahydrofolic acid’ OR ‘serum folate’/exp OR ‘serum folate’ OR’ red cell folate’/exp OR ‘red cell folate’ OR ‘erythrocyte

22

Population Search Terms

folate’/exp OR ‘erythrocyte folate’ OR ‘homocysteine’/exp OR ‘homocysteine’ OR ‘Hcy’) AND (‘testing’/exp OR ‘testing’ OR ‘haematologic test*’/exp OR ‘haematologic test*’)ANDLimits – [humans]/lim AND [english]/lim

CochranePopulation – ((MeSH descriptor Paresthesias explode all trees) OR (MeSH descriptor Peripheral Neuropathy explode all trees) OR (MeSH descriptor Combined Systems Disease explode all trees) OR ((paresthesias) OR (paresthesias):ti,ab,kw) OR ((peripheral neuropathy) OR (peripheral neuropathy):ti,ab,kw) OR ((combined systems disease) OR (combined systems disease):ti,ab,kw))ANDIntervention – ((MeSH descriptor Vitamin B12 explode all trees) OR (Vitamin B12):ti,ab,kw OR (MeSH descriptor Cobalamin explode all trees) OR (cobalamin):ti,ab,kw OR (MeSH descriptor Cyanocobalamin explode all trees) OR (cyanocobalamin):ti,ab,kw OR (MeSH descriptor Hydroxycobalamin explode all trees) OR (hydroxycobalamin):ti,ab,kw OR (MeSH descriptor Methylcobalamin explode all trees) OR (methylcobalamin):ti,ab,kw OR (MeSH descriptor Methylmalonic acid explode all trees) OR (methylmalonic acid):ti,ab,kw OR (MeSH descriptor Methymalonate explode all trees) OR (methylmalonate):ti,ab,kw OR (MeSH descriptor Malonic acid explode all trees) OR (malonic acid):ti,ab,kw OR (MeSH descriptor Holotranscobalamin explode all trees) OR (holotranscobalamin):ti,ab,kw OR (MeSH descriptor HoloTC explode all trees) OR (holoTC):ti,ab,kw OR (MeSH descriptor Folate explode all trees) OR (folate):ti,ab,kw OR (MeSH descriptor Folic acid explode all trees) OR (folic acid):ti,ab,kw) ) OR (MeSH descriptor Vitamin B9 explode all trees) OR (vitamin B9):ti,ab,kw OR (MeSH descriptor Tetrahydrofolic acid explode all trees) OR (tetrahydrofolic acid):ti,ab,kw) ) OR (MeSH descriptor Methylenetetrahydrofolic acid explode all trees) OR (methylenetetrahydrofolic acid):ti,ab,kw OR (MeSH descriptor Serum folate explode all trees) OR (serum folate):ti,ab,kw) ) OR (MeSH descriptor Red cell folate explode all trees) OR (red cell folate):ti,ab,kw OR (MeSH descriptor Erythrocyte folate explode all trees) OR (erythrocyte folate):ti,ab,kw) ) OR (MeSH descriptor Homocysteine explode all trees) OR (homocysteine):ti,ab,kw ) AND ((MeSH descriptor Testing explode all trees) OR (Testing):ti,ab,kw OR (MeSH descriptor Haematologic test* explode al trees) OR (Haematologic test*):ti,ab,kw)ANDLimits [humans]/lim AND [english]/lim

4. Patients with gastrointestinal and malabsoption diseases

Embase and MedlinePopulation – ((‘atrophic body gastritis’/exp OR ‘atrophic body gastritis’) OR (‘gastrectomy’/exp OR ‘gastrectomy’) OR (‘gastric sleeve’/exp OR ‘gastric sleeve’) OR (‘peptic ulcer’/exp OR ‘peptic ulcer’) OR (‘H. Pylori’/exp OR ‘H. Pylori’) OR (‘dyspepsia’/exp OR ‘dyspepsia’) OR (‘diarrhoea’/exp OR ‘diarrhoea’) OR (‘coeliac disease’/exp OR ‘coeliac

23

Population Search Terms

disease’) OR (‘Crohn’s disease’/exp OR ‘Crohn’s disease’) OR (‘tapeworms’/exp OR ‘tapeworms’))ANDIntervention – (Vit*B12 OR ‘vitamin B12’/exp OR’ vitamin B12’ OR cobalamin OR cyanocobalamin OR hydroxycobalamin OR methylcobalamin OR ‘methymalonic acid /exp OR ‘methylmalonic acid’/exp OR ‘methylmalonic acid’ OR ‘MMA OR ‘methylmalonate’ OR ‘malonic acid’ OR ‘holotranscobalamin’/exp OR ‘holotranscobalamin’ OR ‘holoTC’/exp OR ‘holoTC’ OR ‘folate’/exp OR ‘folate’ OR ‘folic acid’/exp OR ‘folic acid’ OR ‘vitamin B9’/exp OR ‘vitamin B9’ OR ‘tetrahydrofolic acid’ OR ‘methylenetetrahydrofolic acid’ OR ‘serum folate’/exp OR ‘serum folate’ OR’ red cell folate’/exp OR ‘red cell folate’ OR ‘erythrocyte folate’/exp OR ‘erythrocyte folate’ OR ‘homocysteine’/exp OR ‘homocysteine’ OR ‘Hcy’) AND (‘testing’/exp OR ‘testing’ OR ‘haematologic test*’/exp OR ‘haematologic test*’)ANDLimits – [humans]/lim AND [english]/lim

CochranePopulation – ((MeSH descriptor Atrophic Body Gastritis explode all trees) OR (MeSH descriptor Gastrectomy explode all trees) OR (MeSH descriptor Gastric Sleeve explode all trees) OR (MeSH descriptor Peptic Ulcer explode all trees) OR (MeSH descriptor H. pylori explode all trees) OR (MeSH descriptor Dyspepsia explode all trees) OR (MeSH descriptor Diarrhoea explode all trees) OR (MeSH descriptor Coeliac Disease explode all trees) OR (MeSH descriptor Crohn’s Disease explode all trees) OR (MeSH descriptor Tapeworms explode all trees) OR ((atrophic body gastritis) OR (atrophic body gastritis):ti,ab,kw OR (gastrectomy) OR (gastrectomy):ti,ab,kw OR (gastric sleeve) OR (gastric sleeve):ti,ab,kw OR (peptic ulcer) OR (peptic ulcer):ti,ab,kw OR (h. pylori) OR (h. pylori):ti,ab,kw OR (dyspepsia) OR (dyspepsia):ti,ab,kw OR (diarrhoea) OR (diarrhoea):ti,ab,kw OR (coeliac disease) OR (coeliac disease):ti,ab,kw OR (Crohn’s disease) OR (Crohn’s disease):ti,ab,kw OR (tapeworms) OR (tapeworms):ti,ab,kw )ANDIntervention – ((MeSH descriptor Vitamin B12 explode all trees) OR (Vitamin B12):ti,ab,kw OR (MeSH descriptor Cobalamin explode all trees) OR (cobalamin):ti,ab,kw OR (MeSH descriptor Cyanocobalamin explode all trees) OR (cyanocobalamin):ti,ab,kw OR (MeSH descriptor Hydroxycobalamin explode all trees) OR (hydroxycobalamin):ti,ab,kw OR (MeSH descriptor Methylcobalamin explode all trees) OR (methylcobalamin):ti,ab,kw OR (MeSH descriptor Methylmalonic acid explode all trees) OR (methylmalonic acid):ti,ab,kw OR (MeSH descriptor Methymalonate explode all trees) OR (methylmalonate):ti,ab,kw OR (MeSH descriptor Malonic acid explode all trees) OR (malonic acid):ti,ab,kw OR (MeSH descriptor Holotranscobalamin explode all trees) OR (holotranscobalamin):ti,ab,kw OR (MeSH descriptor HoloTC explode all trees) OR (holoTC):ti,ab,kw OR (MeSH descriptor Folate explode all trees) OR (folate):ti,ab,kw OR (MeSH descriptor Folic acid explode all trees) OR (folic acid):ti,ab,kw) ) OR (MeSH descriptor Vitamin

24

Population Search Terms

B9 explode all trees) OR (vitamin B9):ti,ab,kw OR (MeSH descriptor Tetrahydrofolic acid explode all trees) OR (tetrahydrofolic acid):ti,ab,kw) ) OR (MeSH descriptor Methylenetetrahydrofolic acid explode all trees) OR (methylenetetrahydrofolic acid):ti,ab,kw OR (MeSH descriptor Serum folate explode all trees) OR (serum folate):ti,ab,kw) ) OR (MeSH descriptor Red cell folate explode all trees) OR (red cell folate):ti,ab,kw OR (MeSH descriptor Erythrocyte folate explode all trees) OR (erythrocyte folate):ti,ab,kw) ) OR (MeSH descriptor Homocysteine explode all trees) OR (homocysteine):ti,ab,kw ) AND ((MeSH descriptor Testing explode all trees) OR (Testing):ti,ab,kw OR (MeSH descriptor Haematologic test* explode al trees) OR (Haematologic test*):ti,ab,kw)ANDLimits [humans]/lim AND [english]/lim

5. Patients with psychiatric disorders

Embase and MedlinePopulation – ((‘dementia’/exp OR ‘dementia’) OR (‘depression’/exp OR ‘depression’) OR (‘psychosis’/exp OR ‘psychosis’) OR (‘Alzheimer’s disease’/exp OR ‘Alzheimer’s disease’))ANDIntervention – (Vit*B12 OR ‘vitamin B12’/exp OR’ vitamin B12’ OR cobalamin OR cyanocobalamin OR hydroxycobalamin OR methylcobalamin OR ‘methymalonic acid /exp OR ‘methylmalonic acid’/exp OR ‘methylmalonic acid’ OR ‘MMA OR ‘methylmalonate’ OR ‘malonic acid’ OR ‘holotranscobalamin’/exp OR ‘holotranscobalamin’ OR ‘holoTC’/exp OR ‘holoTC’ OR ‘folate’/exp OR ‘folate’ OR ‘folic acid’/exp OR ‘folic acid’ OR ‘vitamin B9’/exp OR ‘vitamin B9’ OR ‘tetrahydrofolic acid’ OR ‘methylenetetrahydrofolic acid’ OR ‘serum folate’/exp OR ‘serum folate’ OR’ red cell folate’/exp OR ‘red cell folate’ OR ‘erythrocyte folate’/exp OR ‘erythrocyte folate’ OR ‘homocysteine’/exp OR ‘homocysteine’ OR ‘Hcy’) AND (‘testing’/exp OR ‘testing’ OR ‘haematologic test*’/exp OR ‘haematologic test*’)ANDLimits – [humans]/lim AND [english]/lim

CochranePopulation – ((MeSH descriptor Dementia explode all trees) OR (MeSH descriptor Depression explode all trees) OR (MeSH descriptor Psychosis explode all trees) OR (MeSH descriptor Alzheimer’s disease explode all trees) OR((dementia) OR (dementia):ti,ab,kw) OR ((depression) OR (depression):ti,ab,kw) OR ((psychosis) OR (psychosis):ti,ab,kw) OR ((Alzheimer’s disease) OR (Alzheimer’s disease):ti,ab,kw))ANDIntervention – ((MeSH descriptor Vitamin B12 explode all trees) OR (Vitamin B12):ti,ab,kw OR (MeSH descriptor Cobalamin explode all trees) OR (cobalamin):ti,ab,kw OR (MeSH descriptor Cyanocobalamin explode all trees) OR (cyanocobalamin):ti,ab,kw OR (MeSH descriptor Hydroxycobalamin explode all trees) OR (hydroxycobalamin):ti,ab,kw OR (MeSH descriptor Methylcobalamin explode all trees) OR (methylcobalamin):ti,ab,kw OR (MeSH descriptor Methylmalonic acid explode all trees) OR (methylmalonic acid):ti,ab,kw OR (MeSH descriptor

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Population Search Terms

Methymalonate explode all trees) OR (methylmalonate):ti,ab,kw OR (MeSH descriptor Malonic acid explode all trees) OR (malonic acid):ti,ab,kw OR (MeSH descriptor Holotranscobalamin explode all trees) OR (holotranscobalamin):ti,ab,kw OR (MeSH descriptor HoloTC explode all trees) OR (holoTC):ti,ab,kw OR (MeSH descriptor Folate explode all trees) OR (folate):ti,ab,kw OR (MeSH descriptor Folic acid explode all trees) OR (folic acid):ti,ab,kw) ) OR (MeSH descriptor Vitamin B9 explode all trees) OR (vitamin B9):ti,ab,kw OR (MeSH descriptor Tetrahydrofolic acid explode all trees) OR (tetrahydrofolic acid):ti,ab,kw) ) OR (MeSH descriptor Methylenetetrahydrofolic acid explode all trees) OR (methylenetetrahydrofolic acid):ti,ab,kw OR (MeSH descriptor Serum folate explode all trees) OR (serum folate):ti,ab,kw) ) OR (MeSH descriptor Red cell folate explode all trees) OR (red cell folate):ti,ab,kw OR (MeSH descriptor Erythrocyte folate explode all trees) OR (erythrocyte folate):ti,ab,kw) ) OR (MeSH descriptor Homocysteine explode all trees) OR (homocysteine):ti,ab,kw ) AND ((MeSH descriptor Testing explode all trees) OR (Testing):ti,ab,kw OR (MeSH descriptor Haematologic test* explode al trees) OR (Haematologic test*):ti,ab,kw)ANDLimits [humans]/lim AND [english]/lim

2. What is the evidence regarding the cost implications associated with folate testing?

Table B.2: Search term strategy for clinical question twoPopulation Search Terms

1. Patients undertaking serum vitamin B12/folate testing

Embase and MedlineIntervention – (Vit*B12 OR ‘vitamin B12’/exp OR’ vitamin B12’ OR cobalamin OR cyanocobalamin OR hydroxycobalamin OR methylcobalamin OR ‘methymalonic acid /exp OR ‘methylmalonic acid’/exp OR ‘methylmalonic acid’ OR ‘MMA OR ‘methylmalonate’ OR ‘malonic acid’ OR ‘holotranscobalamin’/exp OR ‘holotranscobalamin’ OR ‘holoTC’/exp OR ‘holoTC’ OR ‘folate’/exp OR ‘folate’ OR ‘folic acid’/exp OR ‘folic acid’ OR ‘vitamin B9’/exp OR ‘vitamin B9’ OR ‘tetrahydrofolic acid’ OR ‘methylenetetrahydrofolic acid’ OR ‘serum folate’/exp OR ‘serum folate’ OR’ red cell folate’/exp OR ‘red cell folate’ OR ‘erythrocyte folate’/exp OR ‘erythrocyte folate’ OR ‘homocysteine’/exp OR ‘homocysteine’ OR ‘Hcy’) AND (‘testing’/exp OR ‘testing’ OR ‘haematologic test*’/exp OR ‘haematologic test*’)ANDEconomic Terms – (‘economic aspect’/exp OR ‘cost benefit analysis’ OR cost* OR ‘cost effectiveness’)ANDLimits – [humans]/lim AND [english]/lim

CochraneIntervention – ((MeSH descriptor Vitamin B12 explode all trees) OR

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Population Search Terms

(Vitamin B12):ti,ab,kw OR (MeSH descriptor Cobalamin explode all trees) OR (cobalamin):ti,ab,kw OR (MeSH descriptor Cyanocobalamin explode all trees) OR (cyanocobalamin):ti,ab,kw OR (MeSH descriptor Hydroxycobalamin explode all trees) OR (hydroxycobalamin):ti,ab,kw OR (MeSH descriptor Methylcobalamin explode all trees) OR (methylcobalamin):ti,ab,kw OR (MeSH descriptor Methylmalonic acid explode all trees) OR (methylmalonic acid):ti,ab,kw OR (MeSH descriptor Methymalonate explode all trees) OR (methylmalonate):ti,ab,kw OR (MeSH descriptor Malonic acid explode all trees) OR (malonic acid):ti,ab,kw OR (MeSH descriptor Holotranscobalamin explode all trees) OR (holotranscobalamin):ti,ab,kw OR (MeSH descriptor HoloTC explode all trees) OR (holoTC):ti,ab,kw OR (MeSH descriptor Folate explode all trees) OR (folate):ti,ab,kw OR (MeSH descriptor Folic acid explode all trees) OR (folic acid):ti,ab,kw) ) OR (MeSH descriptor Vitamin B9 explode all trees) OR (vitamin B9):ti,ab,kw OR (MeSH descriptor Tetrahydrofolic acid explode all trees) OR (tetrahydrofolic acid):ti,ab,kw) ) OR (MeSH descriptor Methylenetetrahydrofolic acid explode all trees) OR (methylenetetrahydrofolic acid):ti,ab,kw OR (MeSH descriptor Serum folate explode all trees) OR (serum folate):ti,ab,kw) ) OR (MeSH descriptor Red cell folate explode all trees) OR (red cell folate):ti,ab,kw OR (MeSH descriptor Erythrocyte folate explode all trees) OR (erythrocyte folate):ti,ab,kw) ) OR (MeSH descriptor Homocysteine explode all trees) OR (homocysteine):ti,ab,kw ) AND ((MeSH descriptor Testing explode all trees) OR (Testing):ti,ab,kw OR (MeSH descriptor Haematologic test* explode al trees) OR (Haematologic test*):ti,ab,kw)ANDEconomic Terms – (((economic aspect) OR (economic aspect):kw) OR ((cost benefit) OR (cost benefit):kw)) OR ((cost effectiveness) OR (cost effectiveness):kw) OR (MeSH descriptor Cost-Benefit Analysis explode all trees) OR (MeSH descriptor Costs and Cost Analysis explode all trees))ANDLimits [humans]/lim AND [english]/lim

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APPENDIX C – SEARCH STRATEGY Search strategies generally include a combination of indexing terms (e.g. MeSH or Emtree headings) and text word terms. Tables B.1 and B.2 set out proposed terms to identify papers in EMBASE. These terms would also be adopted to search other databases as described above. Limits will be employed in a hierarchical manner according to the type of literature being sourced (i.e. Limit 1, and if no relevant literature then Limit 2 and if no relevant literature, then Limit 3).

The selection criteria in Table C.1 will be applied to all publications identified by the literature search to identify studies eligible for inclusion in the systematic review. Study eligibility will be assessed by at least two reviewers.

Table C.1: Inclusion/exclusion criteria for identification of relevant studiesCharacteristic CriteriaPublication type

Clinical studies included. Non-systematic reviews, letters, editorials, animal, in vitro and laboratory studies excluded.Systematic reviewsSystematic reviews that have been superseded will be excludedPrimary studiesPrimary studies published during the search period of included systematic reviews excludedEffectiveness studies Emphasis will be placed on identifying comparative trials however in the absence of such evidence other study designs may be included such as cohort or case series studies (> 20? Patients) prospective, comparative trial >20 patientsSafety studies included if: >50 patients included

Intervention B12/folate testingNo testing

Outcome Studies must report on at least one of the following outcomes: Patient outcomes: (morbidity, mortality, quality of life ) Safety: (adverse physical health outcomes or complications associated with the

procedure )Language Non-English language articles excluded

All eligible studies will be assessed according to the National Health and Medical Research Council (NHMRC) Dimensions of Evidence (Table C.2). There are three main domains: strength of the evidence, size of the effect and relevance of the evidence. The first domain is derived directly from the literature identified for a particular intervention. The last two require expert clinical input as part of their determination.

Table C.2: Dimensions of EvidenceType of evidence DefinitionStrength of the evidence Level

Quality Statistical

precision

The study design used, as an indicator of the degree to which bias has been eliminated by design.The methods used by investigators to minimise bias within a study design.The p-value or, alternatively, the precision of the estimate of the effect (as indicated by the confidence interval). It reflects the degree of certainty about the existence of a true effect.

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Size of effect The distance of the study estimate from the “null” value and the inclusion of only clinically important effects in the confidence interval.

Relevance of evidence The usefulness of the evidence in clinical practice, particularly the appropriateness of the outcome measures used.

One aspect of the ‘strength of the evidence’ domain is the level of evidence, which will be assigned using the NHMRC levels of evidence outlined in Merlin et al 2009.(52) Study quality will be evaluated and reported using the NHMRC Quality Criteria (Table B.3) for randomised controlled trials, cohort studies, case control studies and systematic reviews.

Table C.3: Quality criteria for RCTs, cohort studies, case-control studies and systemic reviews

Study type Quality criteriaRandomised controlled trialsa Was the study double blinded?

Was allocation to treatment groups concealed from those responsible for recruiting the subjects?Were all randomised participants included in the analysis?

Cohort studiesb How were subjects selected for the ‘new intervention’?How were subjects selected for the comparison or control group?Does the study adequately control for demographic characteristics, clinical features and other potential confounding variables in the design or analysis?Was the measurement of outcomes unbiased (i.e. blinded to treatment group and comparable across groups)?Was follow-up long enough for outcomes to occur?Was follow-up complete and were there exclusions from the analysis?

Case-control studiesb How were cases defined and selected?How were controls defined and selected?Does the study adequately control for demographic characteristics and important potential confounders in the design or analysis?Was measurement of exposure to the factor of interest (e.g. the new intervention) adequate and kept blinded to case/control status?Were all selected subjects included in the analysis?

Systematic reviewsc Was an adequate search strategy used?Were the inclusion criteria appropriate and applied in an unbiased way?Was a quality assessment of included studies undertaken?Were the characteristics and results of the individual studies appropriately summarised?Were the methods for pooling the data appropriate?Were sources of heterogeneity explored?

Source: National Health and Medical Research Council (NHMRC), 2000. How to review the evidence: systematic identification and review of the scientific literature, NHMRC, Commonwealth of Australia, Canberra. aBased on work of Schulz et al (1995) and Jadad et al

(1996) bBased on quality assessment instruments developed and being tested in Australia and Canada cBased on articles by Greenhalgh (1997) and Hunt and McKibbon (1997)

Data will be extracted from individual studies using a standardised data extraction form designed specifically for this review. Data extraction will be performed by one reviewer and checked by a second reviewer.

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