mbs review vitamin b12 testing protocol - health.gov.au · bound to haptocorrin (named as...
Post on 19-Aug-2019
212 Views
Preview:
TRANSCRIPT
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
Mechanism of vitamin B12 absorption.................................................................................... 5
Functions of vitamin B12 in the human body .......................................................................... 6
Causes of vitamin B12 deficiencies ........................................................................................ 7
Diseases caused by Vitamin B12 deficiencies ....................................................................... 8
Vitamin B12 testing ................................................................................................................ 8
Prevalence of Vitamin B12 deficiencies in Australia ............................................................. 10
Clinical Flow Chart ............................................................................................................... 12
METHODOLOGY .............................................................................................................. 13
Population, Intervention, Comparator, Outcomes (PICO) .................................................... 13
MBS data ............................................................................................................................. 15
Guideline concordance......................................................................................................... 15
Economic evaluation ............................................................................................................ 15
REFERENCES ..................................................................................................................... 16
APPENDIX A – MBS DATA .............................................................................................. 19
APPENDIX B - SEARCH TERM STRATEGY ............................................................... 21
APPENDIX C – SEARCH STRATEGY ........................................................................... 29
1
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
RBC Red Blood Cell
RCC Review Consultation Committee
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 advising 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 CRC 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 vitamin B12 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 delivered to the RCC include, but are not limited to the following:
(1) Is vitamin B12 testing appropriate for MBS reimbursement?
4
(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
vitamin B12 testing?
(3) What are the clinical indications for medically necessary vitamin B12 testing?
(4) Are current assays used for the detection of serum vitamin B12 levels accurate and reflect
the true status of vitamin B12 in the Australian population?
(5) What are the safety, efficacy, effectiveness of the tests and the effect that the results of the
test 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.
5
BACKGROUND
Mechanism of vitamin B12 absorption
Vitamin B12, also called cobalamin, is a water soluble vitamin that plays a fundamental role
in the normal functioning of the brain and nervous system, and for the formation of blood.
Dietary vitamin B12, obtained from animal food, is bound to animal protein. The acid and
pepsin in the stomach breakdown these protein and release vitamin B12. The free vitamin
B12 then binds a protein called haptocorrin (previously known as Transcobalamin I or R-
Factor or R-protein), which is produced by the salivary glands and parietal cells of the
stomach whose essential function is to protect vitamin B12 from degradation from the acidic
environment of the stomach. In the duodenum, the pancreatic enzymes degrade the
haptocorrin, and vitamin B12 is released again which then binds to the intrinsic factor (IF)
produced by parietal cells. Absorption of vitamin B12 occurs in the terminal ileum (i.e. most
distal part of the small intestine) and is aided by binding the complex to the IF receptor on the
mucosal surface (Figure 1). In addition to this method of absorption, evidence supports the
existence of an alternate pathway that is independent of the IF. This pathway is important in
relation to oral supplementation (approximately 1% of a large oral dose of vitamin B12 is
absorbed by this second mechanism)(1)
Once absorbed, vitamin B12 is bound to two carrier-
proteins in blood: haptocorrin and transcobalamin .The majority of vitamin B12 (70-80%) is
bound to haptocorrin (named as holo-haptocorrin) and is not biologically active. Only less
than 30% of the B12 is bound to trascobalamin II (named as holo-transcobalamin (HoloTC))
which is the active fraction that enters cells for metabolic reactions. Details of these carrier
proteins will be discussed later. The interruption of one or any combination of these steps
places a person at risk of developing vitamin B12 deficiencies.(2)
Figure 1: Vitamin B12 absorption and transport (2)
6
Functions of vitamin B12 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)(3)
. Vitamin B12 is required as a cofactor in
both reactions, whereas folate is required in only one of the reactions (see Figure 2).(2)
Figure 2: The enzymatic reactions that require vitamin B12 and folate (folic acid) as
cofactors (4)
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.(5)
Folate does not play any role in this reaction. Deficiency in vitamin B12 can
lead to increased levels of serum MMA.(2)
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.(2, 6)
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.(2)
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.(2)
It is this metabolic reaction that clearly links the two vitamins and is
7
responsible for the common or shared neuropsychiatric and haematologic disorders discussed
in the following sections.
Vitamin B12: dietary sources, fortification, and supplements
Vitamin B12 is present in animal products such as meat, poultry, fish (including shell fish),
and to a lesser extent milk, cheese and eggs, and it is not present in plant products.(7)
The
recommended dietary allowance for vitamin B12 is 2.4 µg/day (8)
and most individuals can
meet this level through dietary intake.(9)
Table 1 lists some of the foods with substantial
amounts of vitamin B12 along with their vitamin B12 content. Individuals over the age of 50
who have reduced protease secretions in the stomach (as well as strict vegetarians)(10)
obtain
their vitamin B12 from supplements or fortified foods (e.g. fortified cereal) because of the
increased likelihood of food-bound vitamin B12 malabsorption.
Table 1: Examples of dietary sources of vitamin B12 and folate (7, 11)
Type of food Estimated vitamin B12 content (micrograms
µg)
Clams, 3 oz (85 grams) 84.0
Mussels, 3 oz 20.4
Crab, 3 oz 8.8
Salmon, 3 oz 2.4
Beef, 3 oz 2.1
Chicken 0.3
Egg (whole) 0.6
Milk (8 oz, 1 glass) 0.9
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).(12)
Regulations regarding the fortification of foods with vitamin B12 vary
between countries. ANZFSC permits only a limited number of foods to be fortified with
vitamin B12. This includes selected soy milks, yeast spread, and vegetarian meat
analogues.(13)
The risk of toxicity from vitamin B12 intake from supplements and/or fortified foods is
low.(14)
Vitamin B12 is a water soluble vitamin, and therefore any excess intake is usually
excreted in the urine.
Causes of vitamin B12 deficiencies
Table 2 describes causes of vitamin B12 deficiencies which can be divided into four
categories: nutritional deficiency, increased requirements, impaired absorption, and other
gastrointestinal causes.(6, 15)
Table 2: Causes of vitamin B12 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) (16)
Alcoholism (17, 18)
Strict vegan diets (16)
Due to pregnancy
and lactation (22)
Autoimmune disease
with autoantibodies
against the intrinsic
factor (pernicious
anaemia) (23)
(24)
Atrophic body
gastritis (due to
Chronic
gastrointestinal
symptoms e.g.
dyspepsia, recurrent
peptic ulcer,
diarrhoea (2)
Coeliac disease (28)
8
Malnutrition (19)
and
avoidance of
fortified bread due to
coeliac disease (20, 21)
autoantibodies to
gastric parietal
cells)(25)
Gastrectomy (26)
Prolonged use of
acid-suppression
therapy or drugs (27)
Crohn’s disease (29)
Patients with
intestinal surgery
gastric resection,
sleeve or banding
surgery) (30)
Tapeworms and
other intestinal
parasites (26)
Ileocystoplasty (i.e.
a surgical
reconstruction of the
bladder involving
the use of an isolated
segment of ileum to
augment bladder
capacity) (31)
Vitamin B12 deficiency is usually the result of dietary insufficiency and is common in
individuals who are strict vegetarians because vitamin B12 is only present in foods from
animal origin. Because of the complex mechanism of vitamin B12 absorption, causes of
malabsorption may also arise at several levels in the gastrointestinal tract.(24)
At the gastric
level, the most frequent cause of significant vitamin B12 malabsorption leading to deficiency
is pernicious anaemia (PA), which is an autoimmune disorder caused by the frequent
presence of gastric autoantibodies directed against IF and the parietal cells.(32)
PA can affect
both the elderly and young individuals.(33, 34)
Diseases caused by Vitamin B12 deficiencies
Vitamin B12 plays an important role in DNA synthesis and neurologic function.(35)
Deficiency in vitamin B12 is associated with a wide spectrum of haematologic, neurologic
and psychiatric disorders (Table 3) that can often be reversed by early diagnosis and prompt
treatment.(2)
Table 3: Clinical manifestations of vitamin B12 deficiencies
Haematologic (2)
Neurologic(36)
Psychiatric(36)
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(48)
Possible increased
risk of myocardial
infarction and stroke
Vitamin B12 testing
Reliable and accurate assessment of vitamin B12 and folate status is required to determine the
prevalence of deficiencies of these two vitamins in the Australian population and is necessary
9
for developing suitable strategies to prevent these nutritional problems. The haematologic
complications of folate and vitamin B12 deficiencies are identical. Therefore, detecting the
presence of folate or vitamin B12 deficiency, and distinguishing one from the other, depends
critically on laboratory testing. These tests may be used singularly or in combination to
establish the nutritional status and prevalence of deficiencies of the vitamins.
The methods used to assess folate and vitamin B12 status can either measure the:(6)
concentrations of the vitamins in the blood (e.g. serum vitamin B12 levels, serum or
plasma folate levels); and/or
increased levels of metabolites such as MMA and/or homocysteine.
The diagnosis of vitamin B12 deficiency has traditionally been based on measuring the total
serum levels of vitamin B12. There is currently no internationally agreed definition for
vitamin B12 deficiency based on clinical manifestations or on the ‘cut-off’ values that are
used to define vitamin B12 deficiency which vary between 120-200 pmol/L. These could be
partly because the analytical methods for vitamin B12 are not standardised and the results are
variable among different methods. In addition, vitamin B12 carrier protein concentrations can
vary in different individuals. Vitamin B12 is carried on two distinct binding proteins in
plasma. (6, 38)
Transcobalamin II: binds vitamin B12 to form a complex called holotranscobalamin
(holoTC). HoloTC binds only 20–30% of vitamin B12 circulating in the blood, but is
responsible for delivery of vitamin B12 to cells and is considered to be the functionally
important fraction, thus it is named “active-B12” in layman’s term. HoloTC levels fall in
vitamin B12 deficiency. Therefore, testing for HoloTC can identify low vitamin B12
status before total serum vitamin B12 levels drop.(39, 40)
Haptocorrin: binds the major portion of plasma vitamin B12 which is essentially inert as
far as vitamin B12 delivery to cells is concerned, although it may reflect the general
underlying state of vitamin B12 stores. The complex formed by the binding of
haptocorrin to vitamin B12 is called holo-hapctocorrin (HoloHC) (41)
. Haptocorrin
deficiency is associated with low serum vitamin B12 concentrations.(42)
Research has shown that assays that measure holoTC(43)
are a more reliable indicator for
identifying vitamin B12 deficiency, when used in conjunction with other available tests, such
as serum MMA or homocysteine measurements.(44)
Currently available assays to measure
holoTC are developed by Axis-Shield. This company recently launched a new active-B12
assay (Abbott ARCHITECT) for use in high throughout laboratories.(45)
MMA and
homocysteines are functional markers of vitamin B12 status and levels increase when vitamin
B12 deficiency is present. They are particularly useful when HoloTC or total vitamin B12 are
in the equivocal range and vitamin B12 deficiency can not be ruled out with confidence.
However, many other causes in addition to vitamin B12 deficiency can also raise MMA and
homocyseine. These tests have very high negative predictive value, however, when their
levels are elevated, other causes need to be excluded first before vitamin B12 deficiency can
be made. MMA (in blood or urine specimens) can be measured using high performance
liquid chromatography (HPLC)(46)
but the test is not readily available in Australia. Serum
homocysteine can be performed in most of the laboratories in Australia.
Table 4 compares the three tests that can be used to assess vitamin B12 status.
Table 4: Comparison of the three tests used to measure vitamin B12 (6)
10
Biomarkers Serum/plasma B12 Serum holoTC Serum/plasma MMA
Assessing intake + ++ ++
Sensitivity + + ++
Specificity -- - +
Assessing long term and
short term status of vitamin
B12
+
Long term status
++
Long term and short
term status
++
Long term and short
term
Accepted cutoffs indicating
deficient states
Subclinical
deficiency: vitamin
B-12 <300 pg/mL
(<220 pmol/L)
TC <35 pmol/L >260 nmol/L deficient
Table 4 shows that sensitivity of serum vitamin B12 measurement for detection of vitamin
B12 depletion or deficiency is good overall, but specificity is poor, and the predictive value is
improved when this test is combined with measurement of MMA. One study has shown that
the use of a low serum vitamin B12 level as the sole means of diagnosis of vitamin B12
deficiency may miss up from 10 to 26% of patients with actual tissue B12 deficiency.(4)
The
holoTC assay used on its own is also not very predictive of vitamin B12 deficiency unless it
is used in conjunction with plasma MMA or with the total plasma vitamin B12, and when
combined may provide enhanced predictive power to identify true vitamin B12 deficiency.(47)
The availability of the holoTC assay is currently somewhat limited. Therefore, for an
accurate measure of vitamin B12 status and reserves, it is recommended that serum vitamin
B12 levels are combined with a measure of a metabolic marker of vitamin B12 reserves such
as MMA, holoTC or homocysteine.(48)
Serum vitamin B12 target values
The cut-off value for vitamin B12 deficiency varies markedly between laboratories
worldwide. Table 5 presents the “usual or approximate” reference intervals for vitamin B12
deficiencies.
Table 5: Vitamin B12 (49)
reference intervals
Status Vitamin B12 (pg/ml)†
Normal range 200-900 (130-850 pmole/L)
Deficient < 200* (< 130 pmol/L)
* This is an unsafe range as many in the population exhibit neurological symptoms of deficiency at
much higher concentrations. The lowest concentration to be considered normal is 221 pmol/L.(82)
† pmol/L = 0.738xpg/ml
As discussed earlier, elevated homocysteine levels can be a useful indicator for vitamin B12
deficiency, because serum homocysteine levels increase as vitamin B12 stores fall. Serum
homocysteine levels greater than nine µmol/L suggest the beginning of depleted vitamin B12
reserves and levels greater than 15 µmol/L is indicative of depleted vitamin B12 reserves.(50)
However, caution should be taken with this test as homocysteine levels may also increase
with folate deficiency.(51)
Prevalence of Vitamin B12 deficiencies in Australia
The true prevalence of vitamin B12 deficiency in the general Australian population remains
unknown. The incidence appears to increase with age (>65 years) and with the ubiquitous
use of gastric acid–blocking agents.(52)
An Australian study published in 2012 found 14% of
130 patients living in residential aged care facilities in southern Tasmania were vitamin B12
deficient, with serum B12 levels less than 150 pmol/L.(53)
Another study published in 2006
11
examined the prevalence of low serum vitamin B12 in a representative sample of 3,508
persons aged 50+ years between 1997 and 2000.(54)
Low serum vitamin B12 (< 185 pmol/L)
was found in 22.9% of participants.
12
Clinical Flow Chart
The clinical decision pathway which determines whether vitamin B12 testing should be undertaken is provided in Figures 3.
Figure 3: Clinical flow chart for vitamin B12 testing
Patient presents to clinician (e.g. General
Practitioner, Obstetrician etc)
Does the patient have any of the following
clinical symptoms of vitamin B12 deficiency?
• Vegetarians
• Patients >65
• Institutionalised patients or patients in aged care facilities
• Newborn children of vegetarian or malnourished mothers
• Gastric surgery patients
• Atrophic gastritis patients
• H. Pylori infected patients
• Patients with gastrointestinal disorders e.g. Crohn’s, Coeliac disease
Patient ineligible to claim
benefits under MBS item
numbers 66599 or 66602
Measure Vitamin B12 and
claim MBS item number
66599
Neuromotor symptoms including:
• Paresthesia; or
• Ataxia; or
• Decreased reflexes; or
• Restless leg syndrome; or
• Peripheral neuropathy.
Neuropsychiatric symptoms including:
• Dementia
• Depression
• Psychosis
• Personality changes
Haematological symptoms including:
• Anaemia
• Macrocytic anaemia
• Macrocytosis
• Pernicious anaemia
Does the patient have any of the following risk
factors associated with vitamin B12 deficiency?
Measure Vitamin B12/
and/or folate and claim
MBS item number 66602
Patient ineligible to claim
benefits under MBS item
numbers 66599 or 66602
Does the patient have any of the following
haematological symptoms of vitamin B12 deficiency?
Is Vitamin B12/folate
testing medically
necessary?
No
No
Yes
Yes
Is Vitamin B12/folate
testing medically
necessary?
Yes
Yes
No
No
13
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 (90)
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 B12 testing are shown in Table 6.
14
Table 6: Clinical research questions for the vitamin B12 testing
Population Intervention Comparator Outcomes
(1) General Health population
(includes pregnant women,
elderly, alcoholics, vegetarians)
Vitamin B12 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 vitamin B12 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, reviews relevant to the review of vitamin B12 testing.
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 vitamin B12 testing?
(2) What is the strength of evidence for the effectiveness of vitamin B12 testing in improving
outcomes in each target population (e.g. children, pregnant women, elderly, vegetarians,
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 vitamin B12 testing in each target population? How do
safety and quality outcomes of vitamin B12 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 testing
services in each target population across the patient journey?
(5) What is the evidence regarding the cost implications associated with vitamin B12 testing
in each target population compared with not testing?
15
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 vitamin B12 testing MBS item numbers 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 the 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 vitamin B12 testing
in each target population across the patient journey?
(2) Is the current fee structure associated with these items appropriate?
16
REFERENCES
1. Elia M. Oral or parenteral therapy for B12 deficiency. Lancet. 1998 Nov 28;352(9142):1721-2.
2. Oh R, Brown DL. Vitamin B12 deficiency. American family physician. 2003 Mar 1;67(5):979-86.
3. Wikipedia. Cofactor (biochemistry). 2012; Available from:
http://en.wikipedia.org/wiki/Cofactor_(biochemistry).
4. Stabler SP. Screening the older population for cobalamin (vitamin B12) deficiency. J Am Geriatr Soc.
1995 Nov;43(11):1290-7.
5. center UoMM. Methylmalonic acid. 2012; Available from:
http://www.umm.edu/ency/article/003565.htm.
6. Green R. Indicators for assessing folate and vitamin B-12 status and for monitoring the efficacy of
intervention strategies. Am J Clin Nutr. 2011 Aug;94(2):666S-72S.
7. Medicine Io, Board FaN. Dietary Reference Intakes: Thiamin, riboflavin, niacin, vitamin B6, folate,
vitamin B12, pantothenic acid, biotin, and choline. Washington, DC1998.
8. National Health and Medical Research Council, Health. NZMo. Nutrient reference values for Australia
and New Zealand including recommended dietary intakes. Canberra, ACT2006; Available from:
http://www.nhmrc.gov.au/guidelines/publications/n35-n36-n37 (accessed May 2012). .
9. Watanabe F. Vitamin B12 sources and bioavailability. Exp Biol Med (Maywood). 2007
Nov;232(10):1266-74.
10. Gilsing AM, Crowe FL, Lloyd-Wright Z, Sanders TA, Appleby PN, Allen NE, et al. Serum
concentrations of vitamin B12 and folate in British male omnivores, vegetarians and vegans: results from
a cross-sectional analysis of the EPIC-Oxford cohort study. Eur J Clin Nutr. 2010 Sep;64(9):933-9.
11. US Department of Agriculture ARS. USDA National Nutrient Database for Standard Reference, Release
24. 2011; Available from: http://www.ars.usda.gov/ba/bhnrc/ndl.
12. Food Standards ANZ. Adding vitamins and minerals to food. 2012; Available from:
http://www.foodstandards.gov.au/consumerinformation/fortification.cfm.
13. Zealand FSAN. NUTTAB 2010 online searchable database. 2012; Available from:
http://www.foodstandards.gov.au/consumerinformation/nuttab2010/nuttab2010onlinesearchable
database/onlineversion.cfm (accessed Nov 2011). .
14. Hathcock JN. Vitamins and minerals: efficacy and safety. Am J Clin Nutr. 1997 Aug;66(2):427-37.
15. Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care
physician. Arch Intern Med. 1999 Jun 28;159(12):1289-98.
16. Mangels R MV, Messina M. The dietitians’ guide to vegetarian diets: issues and applications. 3rd ed.
Sudbury M, editor: Jones & Bartlett Learning; 2010.
17. Halsted CH. Folate deficiency in alcoholism. Am J Clin Nutr. 1980 Dec;33(12):2736-40.
18. Lindenbaum J. Folate and vitamin B12 deficiencies in alcoholism. Semin Hematol. 1980 Apr;17(2):119-
29.
19. Nkrumah FK, Nathoo KJ, Sanders DM. Iron, folate and vitamin B12 in severe protein-energy
malnutrition. Cent Afr J Med. 1988 Mar;34(3):39-43.
20. Thompson T. Folate, iron, and dietary fiber contents of the gluten-free diet. J Am Diet Assoc. 2000
Nov;100(11):1389-96.
21. Malterre T. Digestive and nutritional considerations in celiac disease: could supplementation help?
Altern Med Rev. 2009 Sep;14(3):247-57.
22. Higgins JR, Quinlivan EP, McPartlin J, Scott JM, Weir DG, Darling MR. The relationship between
increased folate catabolism and the increased requirement for folate in pregnancy. Bjog. 2000
Sep;107(9):1149-54.
23. Gueant JL, Safi A, Aimone-Gastin I, Rabesona H, Bronowicki JP, Plenat F, et al. Autoantibodies in
pernicious anemia type I patients recognize sequence 251-256 in human intrinsic factor. Proc Assoc Am
Physicians. 1997 Sep;109(5):462-9.
24. 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.
25. 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.
26. Green R MJ. Handbook of Vitamins. 4th ed. Zempleni J RR, editor. Boca Raton, FL: Taylor & Francis
Group; 2007.
17
27. Schubert ML. Gastric secretion. Curr Opin Gastroenterol. 2007 Nov;23(6):595-601.
28. 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.
29. 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.
30. Aarts EO, Janssen IM, Berends FJ. The gastric sleeve: losing weight as fast as micronutrients? Obes
Surg. 2011 Feb;21(2):207-11.
31. 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.
32. Kapadia CR. Vitamin B12 in health and disease: part I--inherited disorders of function, absorption, and
transport. Gastroenterologist. 1995 Dec;3(4):329-44.
33. Hershko C, Ronson A, Souroujon M, Maschler I, Heyd J, Patz J. Variable hematologic presentation of
autoimmune gastritis: age-related progression from iron deficiency to cobalamin depletion. Blood. 2006
Feb 15;107(4):1673-9.
34. Lahner E, Annibale B. Pernicious anemia: new insights from a gastroenterological point of view. World J
Gastroenterol. 2009 Nov 7;15(41):5121-8.
35. Allen RH, Stabler SP, Savage DG, Lindenbaum J. Metabolic abnormalities in cobalamin (vitamin B12)
and folate deficiency. Faseb J. 1993 Nov;7(14):1344-53.
36. 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.
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. Herzlich B, Herbert V. Depletion of serum holotranscobalamin II. An early sign of negative vitamin B12
balance. Lab Invest. 1988 Mar;58(3):332-7.
40. Herrmann W, Obeid R, Schorr H, Geisel J. Functional vitamin B12 deficiency and determination of
holotranscobalamin in populations at risk. Clin Chem Lab Med. 2003 Nov;41(11):1478-88.
41. Morkbak AL, Poulsen SS, Nexo E. Haptocorrin in humans. Clin Chem Lab Med. 2007;45(12):1751-9.
42. Carmel R. Mild transcobalamin I (haptocorrin) deficiency and low serum cobalamin concentrations. Clin
Chem. [Research Support, U.S. Gov't, P.H.S.]. 2003 Aug;49(8):1367-74.
43. Ulleland M, Eilertsen I, Quadros EV, Rothenberg SP, Fedosov SN, Sundrehagen E, et al. Direct assay for
cobalamin bound to transcobalamin (holo-transcobalamin) in serum. Clin Chem. 2002 Mar;48(3):526-32.
44. Green R. Metabolite assays in cobalamin and folate deficiency. Bailliere's clinical haematology. 1995
Sep;8(3):533-66.
45. Axis-Shield. Active-B12 the next level of vitamin B12 testing. 2012; Available from: http://www.active-
b12.com/Assays-Active-B12.
46. Kara N, Senes M, Coskun O, Inan L, Saydam G, Yucel D. Urinary methylmalonic acid levels in patients
with acute ischemic stroke. Clin Biochem. 2009 May;42(7-8):578-83.
47. Miller JW, Garrod MG, Rockwood AL, Kushnir MM, Allen LH, Haan MN, et al. Measurement of total
vitamin B12 and holotranscobalamin, singly and in combination, in screening for metabolic vitamin B12
deficiency. Clin Chem. 2006 Feb;52(2):278-85.
48. Lindenbaum J, Savage DG, Stabler SP, Allen RH. Diagnosis of cobalamin deficiency: II. Relative
sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. American
journal of hematology. 1990 Jun;34(2):99-107.
49. Vorvick LaM, J. Vitamin B12 levels-Results. 2010; Available from:
http://www.umm.edu/ency/article/003705res.htm.
50. Ubbink J. What is a desirable homocysteine level? . In: Carmel R JD, editor. Homocysteine in health and
disease. Cambridge, UK: Cambridge University Press; 2001. p. 485-90.
51. Selhub J. Homocysteine metabolism. Annu Rev Nutr. 1999;19:217-46.
52. Bradford GS, Taylor CT. Omeprazole and vitamin B12 deficiency. The Annals of pharmacotherapy.
1999 May;33(5):641-3.
53. Mirkazemi C, Peterson GM, Tenni PC, Jackson SL. Vitamin B12 deficiency in Australian residential
aged care facilities. J Nutr Health Aging. 2012 Mar;16(3):277-80.
18
54. Flood VM, Smith WT, Webb KL, Rochtchina E, Anderson VE, Mitchell P. Prevalence of low serum
folate and vitamin B12 in an older Australian population. Aust N Z J Public Health. 2006 Feb;30(1):38-
41.
55. Richardson WS, Wilson MC, Nishikawa J, Hayward RS. The well-built clinical question: a key to
evidence-based decisions. ACP J Club. 1995 Nov-Dec;123(3):A12-3.
56. Merlin T, Weston A, Tooher R. Extending an evidence hierarchy to include topics other than treatment:
revising the Australian 'levels of evidence'. BMC Med Res Methodol. 2009;9:34.
57. NHMRC. NHMRC levels of evidence and grades for recommendations for developers of guidelines.
[Internet]. Canberra, ACT: National Health and Medical Research Council; 2009. Available from:
http://www.nhmrc.gov.au/_files_nhmrc/file/guidelines/evidence_statement_form.pdf.
19
APPENDIX A – MBS DATA
The MBS item numbers relevant to vitamin B12 testing
Table A.1 shows the two MBS item number for vitamin B12 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 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 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 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 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 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).
20
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
Figure A.3 shows the benefits paid for vitamin B12 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
21
APPENDIX B - SEARCH TERM STRATEGY
Clinical questions
1. What is the safety and effectiveness of vitamin B12 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
22
Population 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
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
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) )
23
Population 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
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
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
24
Population 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
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
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
25
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
26
Population Search Terms
Limits [humans]/lim AND [english]/lim
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
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
27
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 vitamin B12 testing?
Table B.2: Search term strategy for clinical question two
Population Search Terms
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
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
28
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
29
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.
30
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.(91)
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.
top related