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
Lisa Fodero
Diah Elhassen
HealthConsult
HealthConsult
HealthConsult
Project Director
Project Manager
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: 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 ............................................................... 19
APPENDIX C – SEARCH STRATEGY ........................................................................... 27
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
1
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.
2
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?
3
(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.
4
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.
5
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
Lentils (1/2 cup cooked)
Spinach (1/2 cup cooked)
Tomato juice (1 cup)
Orange juice (1 cup)
Green peas (1/2 cup cooked)
Strawberries
Baked beans (1 cup)
Banana (1 medium)
Estimated folate content (micrograms µg)
179
115
49
47
47
40
30
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)
6
Table 2: Causes of folate deficiencies
Increased
requirements
Poor intake of meats  Due to pregnancy
and dairy products in
and lactation (31)
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)
Nutritional deficiency




Impaired absorption
 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)
Other gastrointestinal
causes
 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
7
cofactor for the enzyme that mediates the conversion of homocysteine to methionine (see
Figure 2).
Table 3: Clinical manifestations of folate deficiencies
Haematologic (5)
 Megaloblastic
anaemia
 Panycytopenia
(Leukopenia,
thrombocytopenia)
 Pernicious anaemia
(i.e. large immature
RBCs)
Neurologic(21)
 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)





Psychiatric(41)
Irritability,
personality change
Mild memory
impairment,
dementia
depression
psychosis
Alzheimer’s
Disease(32)
Cardiovascular (37, 38)
 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 3171422 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)
8
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
Normal range
deficient
Folate (ng/ml)‡
3-20
< 3 (7 nmol/L)
RBC folate (ng/ml RBC)
140-628
< 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.
9
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.
Does the patient have any of the following
haematological symptoms of folate deficiency?
• anaemia; and/or
• macrocytosis.
No Yes
Patient ineligible to claim
benefits under MBS item
numbers 66599 or 66602
Does the patient have any of the following risk
factors associated with folate deficiency?
•
•
•
•
•
patients with coeliac disease; and/or
pregnancy; and/or
dietary deficiency; and/or
alcoholism; and/or
malignancy (e.g. leukaemia).
Is Vitamin B12/folate
testing medically
necessary?
Yes
Measure Vitamin B12
and/or folate and claim
MBS item 66602 or 66599
No
10
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.
11
Table 5: Clinical research questions for the folate testing
Population
(1) General Health population
(includes pregnant women,
elderly, alcoholics, vegetarians)
Intervention
Comparator
Safety
 Complications associated with
the procedure (e.g. infection,
needle injuries)
Effectiveness
(2) Infants with metabolic disease
(3) Patients with anaemia and
haematologic diseases
Folate testing
(4) Patients with neurologic
disease
(5) Patients with gastrointestinal
and malabsorption disorders
Outcomes
Supplementation
 Physical health outcomes as a
consequence of the procedure
(e.g. all-cause mortality,
anaemia, NTDs, CVD,
neuropathy, depression and
dementia).
(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?
12
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 costeffectiveness 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?
13
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serum in an elderly male population: association with atrophic gastritis and Helicobacter pylori infection.
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gastrointestinal health and disease. Eur Rev Med Pharmacol Sci. 2012 Mar;16(3):376-85.
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Yakut M, Ustun Y, Kabacam G, Soykan I. Serum vitamin B12 and folate status in patients with
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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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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.
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Ramos MI, Allen LH, Mungas DM, Jagust WJ, Haan MN, Green R, et al. Low folate status is associated
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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.
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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.
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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.
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Yang HT, Lee M, Hong KS, Ovbiagele B, Saver JL. Efficacy of folic acid supplementation in
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Lindenbaum J, Healton EB, Savage DG, Brust JC, Garrett TJ, Podell ER, et al. Neuropsychiatric
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journal of medicine. 1988 Jun 30;318(26):1720-8.
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Cook S-HDaJD. Laboratory reference range values. 2005.
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Guidelines on the investigation and diagnosis of cobalamin and folate deficiencies. A publication of the
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Arsenault JE, Mora-Plazas M, Forero Y, Lopez-Arana S, Baylin A, Villamor E. Hemoglobin
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Louey W LZ, and Sikaris KA. Which Blood Collection Tube is Better for Homocysteine.
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Galloway M, Rushworth L. Red cell or serum folate? Results from the National Pathology Alliance
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Potential benefits and risks for the elderly population. Jama. 1996 Dec 18;276(23):1879-85.
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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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Richardson WS, Wilson MC, Nishikawa J, Hayward RS. The well-built clinical question: a key to
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15
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
66599
MBS Item Number description
Serum B12 or red cell folate and, if required, serum folate
Schedule Fee: $23.75 Benefit: 75% = $17.85 85% = $20.20
Serum B12 and red cell folate and, if required, serum folate
66602
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
66599
66602
Type of date
Item Start Date
Description Start Date
Item Start Date
Description Start Date
Date
01-Nov-1998
01-Mar-1999
01 Nov 1998
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
66599
66602
Total
08/09
382,241
1,476,465
1,858,706
Financial year
09/10
10/11
399,282
447,211
1,586,968
1,667,155
1,986,250
2,114,366
11/12
520,688
1,821,490
2,342,178
12/13
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
16
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
17
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.
Benefits paid for MBS item numbers 6599 and
66602
Figure A.3: Benefits paid for MBS item numbers 66599 and 66602 since 2000/01
80,000,000
70,000,000
60,000,000
50,000,000
40,000,000
30,000,000
20,000,000
10,000,000
0
00/01
01/02
02/03
03/04
04/05
66599
05/06
06/07
07/08
08/09
09/10
10/11
11/12
66602
Source: Department of Human Services Medicare
18
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
1. General healthy
population
Search Terms
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
19
Population
2. Patients diagnosed
with anaemia
Search Terms
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
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
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 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) )
20
Population
3. Patients with
neurologic disease
Search Terms
AND NOT ((MeSH descriptor Iron deficiency anaemia) OR (iron
deficiency anaemia):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
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
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
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
21
Population
4. Patients with
gastrointestinal and
malabsoption
diseases
Search Terms
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
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) )
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
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
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
22
Population
Search Terms
‘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 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
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) )
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
23
Population
5. Patients with
psychiatric
disorders
Search Terms
Limits [humans]/lim AND [english]/lim
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
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 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
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) )
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
24
Population
Search Terms
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. What is the evidence regarding the cost implications associated with folate testing?
Table B.2: Search term strategy for clinical question two
Population
Search Terms
1. Patients undertaking Embase and Medline
serum vitamin
Intervention – (Vit*B12 OR ‘vitamin B12’/exp OR’ vitamin B12’
B12/folate testing
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
Economic Terms – (‘economic aspect’/exp OR ‘cost benefit
analysis’ OR cost* OR ‘cost effectiveness’)
AND
Limits – [humans]/lim AND [english]/lim
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) )
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
25
Population
Search Terms
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
Limits [humans]/lim AND [english]/lim
26
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
Clinical studies included. Non-systematic reviews, letters, editorials, animal, in vitro
Publication
and laboratory studies excluded.
type
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
Studies must report on at least one of the following outcomes:
Outcome
 Patient outcomes: (morbidity, mortality, quality of life )
 Safety: (adverse physical health outcomes or complications associated with the
procedure )
Non-English language articles excluded
Language
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
Strength of the
evidence
 Level


Quality
Statistical
precision
Definition
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.
27
Size of effect
Relevance of evidence
The distance of the study estimate from the “null” value and the inclusion
of only clinically important effects in the confidence interval.
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
Randomised controlled trialsa
Cohort studiesb
Case-control studiesb
Systematic reviewsc
Quality criteria
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?
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?
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?
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.
28