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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 Director

Lisa Fodero HealthConsult Project Manager

Diah Elhassen HealthConsult Research Analyst

HealthConsult Pty Ltd

Head Office: 4409/93 Liverpool Street, Sydney, New South Wales, 2000

Phone (02) 9261 3707: Fax (02) 9261 3705: Email: [email protected]

mailto:[email protected]

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

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ABBREVIATIONS

µg Microgram

AD Alzheimer’s Disease

AIHW Australian Institute of Health and Welfare

ANZFSC Australia and New Zealand Food Standards Code

CMFM Comprehensive Management Framework for the MBS

CoA Coenzyme A

CVD Cardiovascular disease

Department Department of Health and Ageing

DNA Deoxyribonucleic acid

ESC Evaluation Sub-Committee (of MSAC)

FDA Food and Drug Administration

HPLC High performance liquid chromatography

holoTC Holotranscobalamin II

IF Intrinsic factor

MSAC Medical Services Advisory Committee

MBS Medicare Benefits Schedule

MMA Methylmalonic acid

ng/ml Nanogram per millilitre

NTD Neural Tube Defects

oz Ounce

PA Pernicious anaemia

PASC Protocol Advisory Sub-Committee

PBS Pharmaceutical Benefits Scheme

pg/ml Picogram per millilitre

PICO Population, intervention, comparator, outcome

Pmol/L Picomole per Litre

RCC Review Consultation Committee

RBC Red Blood Cell

RDA Recommended Dietary Allowance

TGA Therapeutic Goods Administration

2

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.

3

Principles to Guide MBS Reviews

Reviews 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 Review

To 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?

(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?

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(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 Stakeholders

The 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.

http://www.msac.gov.au/

5

BACKGROUND

Mechanism of folate absorption

Folate 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 body

In 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

responsible for the common or shared neuropsychiatric and haematologic disorders discussed

in the following sections.

6

Folate: dietary sources, fortification, and supplements

Folate 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) 179

Spinach (1/2 cup cooked) 115

Tomato juice (1 cup) 49

Orange juice (1 cup) 47

Green peas (1/2 cup cooked) 47

Strawberries 40

Baked beans (1 cup) 30

Banana (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 deficiencies

Table 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)

http://ods.od.nih.gov/factsheets/showterm.aspx?tID=344

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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 deficiencies

The 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

8

cofactor for the enzyme that mediates the conversion of homocysteine to methionine (see

Figure 2).

Table 3: Clinical manifestations of folate deficiencies

Haematologic (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 testing

Tests 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)

9

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 values

The 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 Australia

The 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.

10

Clinical Flow Chart

The 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

11

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; and

o 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.

12

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?

13

MBS data

MBS 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 concordance

An 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 evaluation

Only 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?

14

REFERENCES

1. Halsted CH. The intestinal absorption of dietary folates in health and disease. Journal of the American

College of Nutrition. 1989 Dec;8(6):650-8.

2. Aufreiter S, Gregory JF, 3rd, Pfeiffer CM, Fazili Z, Kim YI, Marcon N, et al. Folate is absorbed across

the colon of adults: evidence from cecal infusion of (13)C-labeled [6S]-5-formyltetrahydrofolic acid. Am

J Clin Nutr. 2009 Jul;90(1):116-23.

3. Gregory JF, 3rd, Williamson J, Liao JF, Bailey LB, Toth JP. Kinetic model of folate metabolism in

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Sudbury M, editor: Jones & Bartlett Learning; 2010.

20. Halsted CH. Folate deficiency in alcoholism. Am J Clin Nutr. 1980 Dec;33(12):2736-40.

21. Lindenbaum J. Folate and vitamin B12 deficiencies in alcoholism. Semin Hematol. 1980 Apr;17(2):119-

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malnutrition. Cent Afr J Med. 1988 Mar;34(3):39-43.

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Nov;100(11):1389-96.

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Altern Med Rev. 2009 Sep;14(3):247-57.

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increased folate catabolism and the increased requirement for folate in pregnancy. Bjog. 2000

Sep;107(9):1149-54.

26. Gueant JL, Safi A, Aimone-Gastin I, Rabesona H, Bronowicki JP, Plenat F, et al. Autoantibodies in

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Physicians. 1997 Sep;109(5):462-9.

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.

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.

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http://www.umm.edu/ency/article/003565.htm

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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.

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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

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36. Wang HX, Wahlin A, Basun H, Fastbom J, Winblad B, Fratiglioni L. Vitamin B(12) and folate in

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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

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

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revising the Australian 'levels of evidence'. BMC Med Res Methodol. 2009;9:34.

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evidence-based decisions. ACP J Club. 1995 Nov-Dec;123(3):A12-3.

http://www.nhmrc.gov.au/_files_nhmrc/file/guidelines/evidence_statement_form.pdf

16

APPENDIX A – MBS DATA

The MBS item numbers relevant to folate testing

Table 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 description

66599 Serum B12 or red cell folate and, if required, serum folate

Schedule Fee: $23.75 Benefit: 75% = $17.85 85% = $20.20

66602 Serum B12 and red cell folate and, if required, serum folate

Schedule Fee: $43.25 Benefit: 75%=$32.45 85%=$36.80

Both 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 system

Table 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 Date

66599 Item Start Date 01-Nov-1998

Description Start Date 01-Mar-1999

66602 Item Start Date 01 Nov 1998

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

MBS utilisation and expenditure

Utilisation 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 no Financial year

08/09 09/10 10/11 11/12 12/13

66599 382,241 399,282 447,211 520,688

66602 1,476,465 1,586,968 1,667,155 1,821,490

Total 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

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

17

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

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

19

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

Source: Department of Human Services Medicare

0

10,000,000

20,000,000

30,000,000

40,000,000

50,000,000

60,000,000

70,000,000

80,000,000

00/01 01/02 02/03 03/04 04/05 05/06 06/07 07/08 08/09 09/10 10/11 11/12

Ben

efi

ts p

aid

fo

r M

BS

ite

m n

um

bers

6599 a

nd

66602

66599 66602

20

APPENDIX B - SEARCH TERM STRATEGY

Clinical questions

1. 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 Medline Population – ((‘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’))

AND

Intervention – (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*’)

AND

Limits – [humans]/lim AND [english]/lim

Cochrane Population – ((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))

AND

Intervention – ((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

21


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)

AND

Limits [humans]/lim AND [english]/lim

2. Patients diagnosed

with anaemia Embase and Medline Population – ((‘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’)

AND













AND


Cochrane Population – ((MeSH descriptor Anaemia explode all trees) OR (MeSH

descriptor Megaloblastic explode all trees) OR (MeSH descriptor

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) )

22


AND NOT ((MeSH descriptor Iron deficiency anaemia) OR (iron

deficiency anaemia):ti,ab,kw)

AND




























AND


3. Patients with

neurologic disease

Embase and Medline Population – ((‘paresthesias’/exp OR ‘paresthesias’) OR (‘peripheral

neuropathy’/exp OR ‘peripheral neuropathy’) OR (‘combined system

disease’/exp OR ‘combined systems disease’))

AND













AND


23


Cochrane Population – ((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))

AND




























AND


4. Patients with

gastrointestinal and

malabsoption

diseases

Embase and Medline Population – ((‘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

disease’) OR (‘Crohn’s disease’/exp OR ‘Crohn’s disease’) OR

(‘tapeworms’/exp OR ‘tapeworms’))

AND








24







AND


Cochrane Population – ((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 )

AND




























AND

25



5. Patients with

psychiatric

disorders

Embase and Medline Population – ((‘dementia’/exp OR ‘dementia’) OR (‘depression’/exp OR

‘depression’) OR (‘psychosis’/exp OR ‘psychosis’) OR (‘Alzheimer’s

disease’/exp OR ‘Alzheimer’s disease’))

AND













AND


Cochrane Population – ((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))

AND

























26





AND


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

Table B.2: Search term strategy for clinical question two


1. Patients undertaking

serum vitamin

B12/folate testing

Embase and Medline Intervention – (Vit*B12 OR ‘vitamin B12’/exp OR’ vitamin B12’

OR cobalamin OR cyanocobalamin OR hydroxycobalamin OR


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*’)

AND

Economic Terms – (‘economic aspect’/exp OR ‘cost benefit

analysis’ OR cost* OR ‘cost effectiveness’)

AND


Cochrane Intervention – ((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) )


B9):ti,ab,kw OR (MeSH descriptor Tetrahydrofolic acid explode all

trees) OR (tetrahydrofolic acid):ti,ab,kw) ) OR (MeSH descriptor


(methylenetetrahydrofolic acid):ti,ab,kw OR (MeSH descriptor

27


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)

AND

Economic 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))

AND


28

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 studies

Characteristic Criteria

Publication

type

Clinical studies included. Non-systematic reviews, letters, editorials, animal, in vitro

and laboratory studies excluded.

Systematic reviews

Systematic reviews that have been superseded will be excluded

Primary studies

Primary studies published during the search period of included systematic reviews

excluded

Effectiveness 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 patients

Safety studies included if:

>50 patients included

Intervention B12/folate testing

No 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 Evidence

Type of evidence Definition

Strength 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.

29

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 criteria

Randomised 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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