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MBS Review

Vitamin B12 Testing

Protocol

July 2013

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

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ABBREVIATIONS

µg Microgram

AD Alzheimer’s Disease

AIHW Australian Institute of Health and Welfare

ANZFSC Australia and New Zealand Food Standards Code

CMFM Comprehensive Management Framework for the MBS

CoA Coenzyme A

CVD Cardiovascular disease

Department Department of Health and Ageing

DNA Deoxyribonucleic acid

ESC Evaluation Sub-Committee (of MSAC)

FDA Food and Drug Administration

HPLC High performance liquid chromatography

holoTC Holotranscobalamin II

IF Intrinsic factor

MSAC Medical Services Advisory Committee

MBS Medicare Benefits Schedule

MMA Methylmalonic acid

ng/ml Nanogram per millilitre

NTD Neural Tube Defects

oz Ounce

PA Pernicious anaemia

PASC Protocol Advisory Sub-Committee

PBS Pharmaceutical Benefits Scheme

pg/ml Picogram per millilitre

PICO Population, intervention, comparator, outcome

Pmol/L Picomole per Litre

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?

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(2) What are the expected patient health outcomes with regard to patient groups, type of

intervention and practitioners ordering and performing (accreditation and training) the

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.

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

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)

http://en.wikipedia.org/wiki/Brain

http://en.wikipedia.org/wiki/Nervous_system

http://en.wikipedia.org/wiki/Blood

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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)

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

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?


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:


in each target population across the patient journey?

(2) Is the current fee structure associated with these items appropriate?

16

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34. Lahner E, Annibale B. Pernicious anemia: new insights from a gastroenterological point of view. World J

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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

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37. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels

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38. Carmel R, Green R, Rosenblatt DS, Watkins D. Update on cobalamin, folate, and homocysteine.

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39. Herzlich B, Herbert V. Depletion of serum holotranscobalamin II. An early sign of negative vitamin B12

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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-

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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:

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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.

http://www.active-b12.com/Assays-Active-B12

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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.

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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


OR (MeSH descriptor Methylcobalamin explode all trees) OR

(methylcobalamin):ti,ab,kw OR (MeSH descriptor Methylmalonic acid

explode all trees) OR (methylmalonic acid):ti,ab,kw OR (MeSH

descriptor Methymalonate explode all trees) OR

(methylmalonate):ti,ab,kw OR (MeSH descriptor Malonic acid explode

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

Holotranscobalamin explode all trees) OR (holotranscobalamin):ti,ab,kw

OR (MeSH descriptor HoloTC explode all trees) OR (holoTC):ti,ab,kw

OR (MeSH descriptor Folate explode all trees) OR (folate):ti,ab,kw OR

(MeSH descriptor Folic acid explode all trees) OR (folic acid):ti,ab,kw) )

OR (MeSH descriptor Vitamin B9 explode all trees) OR (vitamin

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

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

Methylenetetrahydrofolic acid explode all trees) OR

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

folate explode all trees) OR (serum folate):ti,ab,kw) ) OR (MeSH

descriptor Red cell folate explode all trees) OR (red cell folate):ti,ab,kw

OR (MeSH descriptor Erythrocyte folate explode all trees) OR

(erythrocyte folate):ti,ab,kw) ) OR (MeSH descriptor Homocysteine

explode all trees) OR (homocysteine):ti,ab,kw ) AND ((MeSH descriptor

Testing explode all trees) OR (Testing):ti,ab,kw OR (MeSH descriptor

Haematologic test* explode al trees) OR (Haematologic test*):ti,ab,kw)

AND

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

2. Patients diagnosed

with anaemia Embase and Medline Population – ((‘anaemia’/exp OR ‘anaemia’ OR ‘anemia’/exp OR

‘anemia’) OR (‘macrocyt*’/exp OR ‘macrocyt*)’ OR (‘megaloblastic

’/exp OR ‘megaloblastic’) OR (‘pernicious’/exp OR ‘pernicious’) OR

(‘pancytopenia’/exp OR ‘pancytopenia’)) AND NOT (‘iron deficiency

anaemia’/exp OR ‘iron deficiency anaemia’)

AND













AND


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

descriptor Megaloblastic explode all trees) OR (MeSH descriptor

Pernicious explode all trees) OR (MeSH descriptor Pancytopenia explode

all trees) OR ((anaemia) OR (anaemia):ti,ab,kw) OR ((megaloblastic) OR

(megaloblastic):ti,ab,kw) OR (macrocyt*) OR ((pernicious) OR

(pernicious):ti,ab,kw) OR ((pancytopenia) OR (pancytopenia):ti,ab,kw) )

23


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

deficiency anaemia):ti,ab,kw)

AND




























AND


3. Patients with

neurologic disease

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

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

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

AND













AND


24


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

(MeSH descriptor Peripheral Neuropathy explode all trees) OR (MeSH

descriptor Combined Systems Disease explode all trees) OR

((paresthesias) OR (paresthesias):ti,ab,kw) OR ((peripheral neuropathy)

OR (peripheral neuropathy):ti,ab,kw) OR ((combined systems disease)

OR (combined systems disease):ti,ab,kw))

AND




























AND


4. Patients with

gastrointestinal and

malabsoption

diseases

Embase and Medline Population – ((‘atrophic body gastritis’/exp OR ‘atrophic body gastritis’)

OR (‘gastrectomy’/exp OR ‘gastrectomy’) OR (‘gastric sleeve’/exp OR

‘gastric sleeve’) OR (‘peptic ulcer’/exp OR ‘peptic ulcer’) OR (‘H.

Pylori’/exp OR ‘H. Pylori’) OR (‘dyspepsia’/exp OR ‘dyspepsia’) OR

(‘diarrhoea’/exp OR ‘diarrhoea’) OR (‘coeliac disease’/exp OR ‘coeliac

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

(‘tapeworms’/exp OR ‘tapeworms’))

AND








25







AND


Cochrane Population – ((MeSH descriptor Atrophic Body Gastritis explode all

trees) OR (MeSH descriptor Gastrectomy explode all trees) OR (MeSH

descriptor Gastric Sleeve explode all trees) OR (MeSH descriptor Peptic

Ulcer explode all trees) OR (MeSH descriptor H. pylori explode all trees)

OR (MeSH descriptor Dyspepsia explode all trees) OR (MeSH descriptor

Diarrhoea explode all trees) OR (MeSH descriptor Coeliac Disease

explode all trees) OR (MeSH descriptor Crohn’s Disease explode all

trees) OR (MeSH descriptor Tapeworms explode all trees) OR ((atrophic

body gastritis) OR (atrophic body gastritis):ti,ab,kw OR (gastrectomy)

OR (gastrectomy):ti,ab,kw OR (gastric sleeve) OR (gastric

sleeve):ti,ab,kw OR (peptic ulcer) OR (peptic ulcer):ti,ab,kw OR (h.

pylori) OR (h. pylori):ti,ab,kw OR (dyspepsia) OR (dyspepsia):ti,ab,kw

OR (diarrhoea) OR (diarrhoea):ti,ab,kw OR (coeliac disease) OR (coeliac

disease):ti,ab,kw OR (Crohn’s disease) OR (Crohn’s disease):ti,ab,kw OR

(tapeworms) OR (tapeworms):ti,ab,kw )

AND




























AND

26



5. Patients with

psychiatric

disorders

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

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

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

AND













AND


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

descriptor Depression explode all trees) OR (MeSH descriptor Psychosis

explode all trees) OR (MeSH descriptor Alzheimer’s disease explode all

trees) OR((dementia) OR (dementia):ti,ab,kw) OR ((depression) OR

(depression):ti,ab,kw) OR ((psychosis) OR (psychosis):ti,ab,kw) OR

((Alzheimer’s disease) OR (Alzheimer’s disease):ti,ab,kw))

AND

























27





AND


2. What is the evidence regarding the cost implications associated with vitamin B12 testing?

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


1. Patients undertaking

serum vitamin

B12/folate testing

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

OR cobalamin OR cyanocobalamin OR hydroxycobalamin OR


acid’/exp OR ‘methylmalonic acid’ OR ‘MMA OR

‘methylmalonate’ OR ‘malonic acid’ OR ‘holotranscobalamin’/exp

OR ‘holotranscobalamin’ OR ‘holoTC’/exp OR ‘holoTC’ OR

‘folate’/exp OR ‘folate’ OR ‘folic acid’/exp OR ‘folic acid’ OR

‘vitamin B9’/exp OR ‘vitamin B9’ OR ‘tetrahydrofolic acid’ OR

‘methylenetetrahydrofolic acid’ OR ‘serum folate’/exp OR ‘serum

folate’ OR’ red cell folate’/exp OR ‘red cell folate’ OR ‘erythrocyte

folate’/exp OR ‘erythrocyte folate’ OR ‘homocysteine’/exp OR

‘homocysteine’ OR ‘Hcy’) AND (‘testing’/exp OR ‘testing’ OR

‘haematologic test*’/exp OR ‘haematologic test*’)

AND

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

analysis’ OR cost* OR ‘cost effectiveness’)

AND


Cochrane Intervention – ((MeSH descriptor Vitamin B12 explode all trees)

OR (Vitamin B12):ti,ab,kw OR (MeSH descriptor Cobalamin

explode all trees) OR (cobalamin):ti,ab,kw OR (MeSH descriptor

Cyanocobalamin explode all trees) OR (cyanocobalamin):ti,ab,kw

OR (MeSH descriptor Hydroxycobalamin explode all trees) OR

(hydroxycobalamin):ti,ab,kw OR (MeSH descriptor

Methylcobalamin explode all trees) OR (methylcobalamin):ti,ab,kw

OR (MeSH descriptor Methylmalonic acid explode all trees) OR

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

Methymalonate explode all trees) OR (methylmalonate):ti,ab,kw

OR (MeSH descriptor Malonic acid explode all trees) OR (malonic

acid):ti,ab,kw OR (MeSH descriptor Holotranscobalamin explode

all trees) OR (holotranscobalamin):ti,ab,kw OR (MeSH descriptor

HoloTC explode all trees) OR (holoTC):ti,ab,kw OR (MeSH

descriptor Folate explode all trees) OR (folate):ti,ab,kw OR (MeSH

descriptor Folic acid explode all trees) OR (folic acid):ti,ab,kw) )


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

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


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

28


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


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.

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