MBS Review Vitamin D Testing Protocol - Department of … Elhassen HealthConsult Research Analyst...

MBS Review

Vitamin D Testing

Protocol

July 2013

This protocol was commissioned by the Department of Health and Ageing

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

Project Team: Joe Scuteri HealthConsult Project Director

Lisa Fodero HealthConsult Project Manager

Diah Elhassen HealthConsult Research Analyst

HealthConsult Pty Ltd

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

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

mailto:[email protected]

CONTENTS

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

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

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

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

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

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

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

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

Vitamin D metabolism and function........................................................................... 5

Vitamin D testing ........................................................................................................ 7

Prevalence of Vitamin D Deficiency in Australia ..................................................... 9

Conditions that may cause vitamin D deficiency .................................................... 9

Incidence and prevalence of diseases relevant to the vitamin D testing review 10

Clinical Flow Chart ................................................................................................... 13

METHODOLOGY ..................................................................................................... 14

Population, Intervention, Comparator, Outcomes (PICO) ................................... 14

MBS data ................................................................................................................... 16

Guideline concordance ............................................................................................ 16

Economic evaluation ............................................................................................... 16

REFERENCES ............................................................................................................ 17

APPENDIX A – MBS DATA ..................................................................................... 21

APPENDIX B - SEARCH TERM STRATEGY ...................................................... 23

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

1

ABBREVIATIONS

1,25-(OH)2D 1,25 Dihydroxy vitamin D

25-(OH)D 25 Hydroxy vitamin D

µg Micro gram (unit of measurement)

CKD Chronic kidney disease

CVD Cardiovascular disease

CMFM Comprehensive Management Framework for the MBS

CRC Consultation Review Committee

Department Department of Health and Ageing

HTA Health technology assessment

IU International Unit

LC-MS Liquid chromatography-Mass spectrometry

MSAC Medical Services Advisory Committee

MBS Medicare Benefits Schedule

MESP MSAC Expert Standing Panel

NIST National Institute of Standards and Technology

nmol/L Nano mole per litre (unit of measurement

OHTAC Ontario Health technology advisory committee

PBS Pharmaceutical Benefits Scheme

PICO Population, intervention, comparator, outcome

PTH Parathyroid Hormone

RCPAQAP Royal College of Pathologists of Australasia Quality Assurance Program

RCT Randomised controlled trials

RDA Recommended Dietary Allowance

UVB Ultraviolet B

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 feed into the MBS

process where appropriate.

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

Consultation Review Committee (CRC), a time limited committee of nominated experts,

determined and chaired by the Department of Health and Ageing (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. The

CRC will provide expertise to the Department in the development of the policy issues paper.

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 CRC 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

CRC, 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

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 the vitamin D 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 CRC, public consultations and also other information that is relevant to the

review including budgetary considerations.

The following questions, to be addressed as part of the stakeholder consultations, are:

(1) What are the appropriate clinical indications for medically necessary vitamin D testing?

(2) What is the strength of evidence for the effectiveness of vitamin D testing in improving

outcomes in each target population across the patient journey?

4

(3) What are the safety and quality implications (including morbidity, mortality and patient

satisfaction) associated with vitamin D testing in each target population?

(4) How do safety and quality outcomes of vitamin D testing vary according to:

a. the difference in testing methodologies?

b. frequency of testing?

(5) What is the evidence regarding the cost implications associated with vitamin D testing in

each target population compared with not testing?

(6) Is the current MBS fee appropriate?

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 report 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

Vitamin D metabolism and function

Vitamin D is a lipid soluble vitamin that acts as a hormone.(1)

It is synthesised in the skin

through exposure to ultraviolet B light (UVB) radiation from sunlight (2)

and may also be

obtained from dietary sources and supplements.(3)

There are two forms of vitamin D(4)

:

vitamin D2 (also known as ergocalciferol), which is present in plants (e.g. mushrooms);

and

vitamin D3 (also known as cholecalciferol), which is the main form obtained from animal

sources (such as some fish) and exposure to sunlight.(5)

Vitamin D supplements are

composed of the D3 form and are manufactured by the irradiation of 7-

Dehydrocholesterol extracted from lanolin found in sheep's wool.(6)

Figure 1 shows that cutaneous synthesis of vitamin D is triggered by the skin’s exposure to

UVB (wavelength 290-315 nm) which converts 7-Dehydrocholesterol present in the skin into

previtamin D3, and which is then converted into vitamin D3.(3)

Experimental data indicates

that exposure of around 15% of the body surface (arms and hands or equivalent) near the

middle of the day will result in the production of about 1000 IU (25 μg) of vitamin D.

Achieving this exposure on most days should generally, though not always, be sufficient to

maintain vitamin D levels in the body.(7)

Factors such as seasons and latitude can play a role

in vitamin D synthesis, for example less vitamin D is synthesised in winter, particularly at

latitudes further from the equator.

Figure 1: Synthesis of vitamin D

Source: adapted from http://gardenofeaden.blogspot.com.au/2012/02/what-is-vitamin-d-deficiency.html

Vitamin D from diet, supplements, or sunlight exposure first undergoes a hydroxylation

reaction in the liver (Figure 1), producing 25-hydroxyvitamin D (25-(OH)D (also known as

6

calcidiol). This is the major circulating form and the metabolite routinely used to assess

overall vitamin D status. Further hydroxylation occurs in the kidney to form the hormonal

and biologically active 1,25-Dihydroxyvitamin D, also known as calcitriol.(5)

This

hydroxylation step can also occur in other tissues.(2, 8)

The renal synthesis of 1,25-

dihydroxyvitamin D is regulated by plasma parathyroid hormone (PTH), serum calcium and

phosphorus levels.(9)

The active compound of vitamin D promotes intestinal calcium and phosphate absorption and

is important in maintaining adequate calcium levels for bone mineralisation, bone growth and

remodelling, and to prevent hypocalcemic tetany (i.e. this is an uncommon condition caused

by an abnormally low level of calcium in the blood).(1, 3, 10)

Serum PTH has an inverse

correlation with absorbed calcium.(11)

Vitamin D deficiency reduces the efficiency of

calcium absorption from the intestines and therefore indirectly result in increased serum

PTH(11)

, which may lead to the mobilisation of calcium from the bone.(12)

Vitamin D dietary sources, fortification and supplements

Vitamin D (D3) is naturally present in small quantities in certain food such as fatty fish

(salmon, herring, tuna, sardines etc.), egg yolks, fish liver oil, and certain types of

mushrooms (see Table 1).(3, 13)

However, most adults are unlikely to obtain more than 5%–

10% of their vitamin D requirement from dietary foods and is therefore insufficient to meet

daily requirements.(14)

Thus, most vitamin D is obtained from exposure to sunlight, some

fortified or unfortified foods, and/or vitamin D supplements.

Table 1: Dietary sources of vitamin D (3)

Type of food Estimated vitamin D content (International Unit

IU)

Salmon (fresh, farmed), 3.5 oz (99 grams) 100-250 IU vitamin D3

600 – 1,000 IU vitamin D3 (wild)

Mackerel, (canned), 3.5 oz (99 grams) 250 IU vitamin D3

Cod liver oil, 1 teaspoon (also contains vitamin A) 400-1,000 IU vitamin D3

Tuna (canned), 3.6 oz (100 grams) 230 IU vitamin D3

Shiitake mushrooms (fresh), 3.5 oz 100 IU vitamin D2 (fresh)

1,600 IU vitamin D2 (sun-dried)

Egg yolk (1 unit) 20 IU vitamin D3 or D2

Food fortification is defined as the process of adding micronutrients, such as vitamins and

minerals, to food as permitted by the Food Standards Code.(15)

Regulations regarding the

fortification of foods with vitamin D varies between countries. In Australia, mandatory

fortification regulations require the addition of vitamin D to margarines and spreads.(15)

In

Canada, which has similar regulations to the United States, vitamin D fortification of milk

(including evaporated and powdered milk), soy milk, and margarine is mandatory.(13)

One

serving (250 ml) of milk contains approximately 44% of the 200 IU adequate daily intake of

vitamin D.(13)

Vitamin D fortification is also permitted for orange juice, meal replacements,

nutritional supplements, and formulated liquid diet.(13, 16)

However, and despite vitamin D

mandatory fortification of foods in North America, a large proportion of the American and

Canadian populations are vitamin D deficient, indicating that limited voluntary fortification

has little impact at a population level.(13, 17)

It is acknowledged that the current (2006) guidelines for recommended dietary intakes (i.e.

adequate intakes) of vitamin D in Australia and New Zealand(18)

are out of date.(19)

The

recently revised recommended daily allowances (RDAs) for vitamin D in the US are 600 IU

7

(15 μg) for people aged 1–70 years and 800 IU (20 μg) for those aged ≥ 71 years, with an

upper limit (that includes a generous safety factor) of 4000 IU (100 μg).(20)

Vitamin D synthesis through the skin can be influenced by several factors such as number of

sunshine hours, time of day, season, latitude and skin colour (due to the amount of melanin in

skin). All these factors determine the amount of UBV that reaches the skin. The season is an

important predictor of serum 25-(OH)D levels.(21, 22)

In an Australian study that looked at

three populations of women in three locations across Australia and covering a broad

latitudinal range (Tasmania, Geelong, and Queensland), vitamin D insufficiency was

common in winter and spring regardless of latitude.(22)

However, latitude plays a significant

role in serum 25-(OH)D levels, and higher prevalence of vitamin D deficiencies is reported in

people living at increasing distances from the Equator.(23)

Vitamin D toxicity is a rare condition that can be caused by excess oral or intramuscular

administration of vitamin D. The current policy of the Institute of Medicine (IOM) has set

the tolerable upper intake level for vitamin D at 100 micrograms (µg) (4000 IU)/d, defining

this as “the highest level of daily nutrient intake that is likely to pose no risks of adverse

health effects to almost all individuals in the general population”. (20)

Vitamin D toxicity

cannot be caused by prolonged exposure of the skin to sunlight, which produces 25-(OH)D

amounts equivalent to daily oral consumption of 250 µg (10,000 IU)/d. The main symptoms

with hypervitaminosis D are hypercalciuria (i.e. a condition of elevated calcium in the urine),

hypercalcaemia (i.e. a condition of elevated calcium in the blood), and calcification of soft

tissues and kidney.(24)

Hypercalcaemia is not seen until serum 25-(OH)D concentrations have

consistently been above 375–500 nmol/L.(25, 26)

Vitamin D testing

A vitamin D test measures either 25-(OH)D, the major circulating metabolite to assess

vitamin D status. or 1,25-Dihydroxyvitamin D(27)

, to assess serum vitamin D level and

metabolism. The 25-(OH)D metabolite has an estimated half-life of approximately two to

three weeks, (5, 27, 28)

and provides a measure of the vitamin D originating from both

cutaneous production and dietary/supplement sources. (5)

Vitamin D stored in other body

tissues are, however, not reflected in the serum 25(OH)D levels.(5)

The 1,25-

dihydroxyvitamin D has a half-life of 15 hours and therefore serum levels of this metabolite

do not accurately indicate the individual’s vitamin D status. Since it is closely regulated by

PTH and the intake of calcium and phosphate, serum levels of 1,25-Dihydroxyvitamin D(5, 13)

may be normal in individuals with vitamin D deficiency(29)

.

There are two different assays for measuring serum levels of 25-(OH)D (30-32)

:

liquid chromatography-tandem mass spectrometry (LC-MS): this is a sensitive and

reasonably specific method for the detection of 25-(OH) D (in its two analyte forms D2

and D3) based on their respective chemical properties. This method has been referred to

as a ‘gold standard’ test, but it is slow and requires expensive equipment and skilled staff.

commercial immunoassays either using radioactive markers or chemical markers (e.g. the Abbott Architect, Diasorin Liasion and the Siemens Centaur): are automated

immunoassays to measure total vitamin D levels. These assays may be cheaper and

quicker to conduct (about half the cost of liquid chromatography). Most are less sensitive

as they do not distinguish between the two metabolites of vitamin D.

8

It is not clear from the literature if the detection of both D2 and D3 metabolites has any

clinical relevance. A systematic review and meta-analysis on the comparison of vitamin D2

and D3 supplementation in raising serum 25-(OH)D status indicated that vitamin D3 is more

efficacious at raising serum 25-(OH)D concentrations than is vitamin D2.(33)

Moreover, some

current automated immunoassays have a limited capacity to detect 25-(OH)D2.(34)

It is

currently accepted in Australia that total 25-(OH)D measurement is appropriate to judge a

patient’s vitamin D status.(35)

Accuracy and precision of Vitamin D testing

Different immunoassays are readily available for measurement of 25-(OH)D3. Prior to the

recent introduction of the standard reference material for 25-(OH)D, called SRM 972

introduced from the National Institute of Standards and Technology (NIST),(36)

there were

numerous publications reporting that different immunoassays may be yielding different

results, with inter-assay variation reaching up to 25% at low serum 25-(OH)D levels (15

nmol/L).(27, 35)

However, with the introduction of the reference standard, the accuracy of the

different immunoassays for the measurement of 25-(OH)D in serum should serve as an

adjunct to quality assurance programs for vitamin D measurements.(37)

The performance of radioimmunoassay and enzyme-linked assays is acceptable, however, the

bias and imprecision of many automated methods may be problematic at the lower, clinically

and analytically important range (< 50 nmol/L) of the assay.(19)

The new reference standard

is available at four different concentrations (called Level 1 – Level 4 by the manufacturer).(36)

The first SRM 972 concentration (Level 1) is prepared from “normal” human serum and is

the only standard that has not been altered through dilutions or enrichments (59.6 nmol/L).

The second concentration (called Level 2) was prepared by diluting Level 1 with horse serum

to achieve a lower 25(OH)D concentration, whereas Level 3 and Level 4 had 25 (OH)D3

added to them.(36)

The development of this reference standard for vitamin D in blood serum

has assisted laboratories to validate the accuracy of their test methods, as well as to validate

new analytical methods as they are developed.(37)

In addition, all Australian and New Zealand laboratories (including those offering 25-(OH)D

testing) are required to be enrolled in external proficiency programs (such as the Royal

College of Pathologists of Australasia Quality Assurance Program (RCPAQAP)), which

allow each laboratory to monitor its performance compared with its peers.(19)

These

standardisation efforts are essential to the reliable diagnosis, evaluation, and treatment of

vitamin D deficiency in a population and help clinicians to more accurately interpret the

results from vitamin D testing.(38)

Serum Vitamin D target values

Some evidence suggests that optimal mineral metabolism, bone density and muscle function

is achieved at serum 25-(OH)D concentrations of greater than 50-60 nmol/L(19, 39-41)

.

However, an optimal serum concentration of vitamin D has not been established and this

value may vary across different stages of life.(5)

Some authors believe that target serum

levels should be above 50 nmol/L (1, 3, 10, 27, 28)

, others believe that it should be above 75

nmol/L.(2, 3, 5, 28, 42)

. One study indicated that 25-(OH)D concentrations <75 nmol/L showed

increased unmineralised bone matrix, making this value an appropriate cut-off for optimal

bone health.(43)

This however may require vitamin D supplementation.(10)

9

Vitamin D deficiency is defined as a serum 25-(OH)D levels below 25 nmol/L (3, 4, 27)

, based

primarily on the risk of rickets in infants and osteomalacia in adults.(44)

Although mild

Vitamin D deficiency is defined as a serum level below 50 nmol/L.(19)

Severe deficiency has

also been defined as a serum level below 12.5 nmol/L.(1, 2, 10)

Table 2 summarises serum

vitamin D concentrations and health.

Table 2: Serum 25-(OH)D concentrations reflective of vitamin status(19)

Vitamin D status Serum vitamin D concentrations nmol/L*

Optimal (19)

>75

Sufficient (19)

50-75

Mild deficiency (45)

25–49

Moderate deficiency (46)

12.5-24

Severe deficiency < 12.5 *1 nmol/L = 0.4 ng/ml

Prevalence of Vitamin D Deficiency in Australia

Two publications have attempted to measure the prevalence of vitamin D deficiency in the

Australian population. The first study was conducted by the Baker IDI Heart and Diabetes

Institute. The population included 11,218 adults aged 25-95 years. The study reported an

estimated 31% of adults in Australia have inadequate vitamin D status (serum 25-(OH)D

levels < 50 nmol/L) and that 4% of the population had severely deficient levels (serum 25-

(OH)D levels < 25 nmol/L). Individuals at greatest risk for deficiency were identified to be

women, the elderly, the obese, people doing less than 2.5 hours of physical activity a week,

and people of non-European background.(47)

The second study, which assessed 24,819

samples taken from a large reference laboratory in NSW between 1st July 2008 and 30

th July

2010, reported that up to 58% of Australians are deficient in vitamin D.(48)

Conditions that may cause vitamin D deficiency

There are several factors reported in the literature that can cause vitamin D deficiency in a

diverse group of individuals. Table 3 summarises the risk factors for vitamin D deficiency.

Table 3: Risk factors for vitamin D deficiency (5)

Reduced sun

exposure Dietary intake Age and disease conditions

Elderly (49)

Darker skin

pigmentation (50)

Winter season (51)

Sunscreen (22)

Shift and indoor

workers

People who

habitually wear

long sleeves,

modest dress

Exclusive

breastfeeding (risk

for the infant) (52)

Obesity (53)

Older age worsened by immobility and aging kidneys

Chronic kidney disease (54, 55)

Malabsorption syndromes/other conditions : Crohn’s

disease, cystic fibrosis, severe liver disease (56)

Drug interactions: anticonvulsants, cimetidine,

thiazides, corticosteroids (57, 58)

Drugs that decrease absorption: mineral oil, laxatives

orlistat, cholestiramine etc.(59)

Genetics (60)

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Incidence and prevalence of diseases relevant to the vitamin D testing review

Table 4 presents the incidence and prevalence of clinical conditions where the literature

indicates that vitamin D testing is recommended.

Table 4: Incidence and prevalence of conditions where vitamin D testing is recommended

Condition Description Prevalence/incidence

Osteoporosis The condition where bone is lost at a higher rate

than its replacement causing to loss of bone

mineral density (61)

692,000 cases (3.4)% (62)

Osteomalacia Softening of bones, inadequate mineralization of

bone matrix, caused by vitamin D deficiency (5,

63)

Data on prevalence is not available

Rickets Inadequate bone mineralisation, disorder

affecting growth plate, caused by vitamin D

deficiency, leading to soft bones, skeletal

deformities, and growth retardation (64)

Australian Paediatric

Surveillance Unit (APSU) study

suggests that the overall

incidence in children </= 15

years of age in Australia was

4.9/100 000/year (65)

Chronic kidney

disease (CKD)

Refers to all conditions of the kidney, lasting at

least three months, where a person has had

evidence of kidney damage and/or reduced kidney

function, regardless of the specific diagnosis of

disease or condition causing the disease. There

are five stages depending on the level of damage (66)

Stages 1-2: 5.6% (66)

Stages 3-5: 7.8% (66)

Crohn’s

disease (and

any

malabsorbtion)

An autoimmune disease (where the body’s

immune system attacks its own healthy body

tissues) affecting the intestines and resulting in

chronic inflammation of the gastrointestinal tract (67)

29.3/100,000 (incidence rate) (68)

Cystic fibrosis A genetic disease affecting the secretory organs,

causing thick, sticky mucus to build up in the

lungs, digestive tract, and other areas of the body.

It is one of the most common chronic lung

diseases in children and young adults (69)

3,200 cases (prevalence) (70)

There is an increasing number of medical conditions associated with low vitamin D status.

Prolonged vitamin D deficiency causes rickets in children (44)

and osteomalacia in adults.(5)

Other symptoms associated with vitamin D deficiency, such as bone pain and muscle

weakness, may be attributed to the decline of vitamin D receptors in skeletal muscle

associated with ageing.(71)

Vitamin D deficiency is classified as one of the risk factors for osteoporosis.(62)

Even though

osteoporosis does not cause death, osteoporotic fractures can lead to premature deaths among

the elderly. In 2007, osteoporosis was listed as the underlying cause of 240 deaths in

Australia. Fractures of hip and pelvis (40.5%) and wrist and forearm (17.1%) were the most

common sites of minimal trauma fractures in 2007–08. The total direct health expenditure

for osteoporosis in 2004-05 was $304 million (Table 5). Over 70% of this was spent to cover

the cost of pharmaceutical medicines ($215 million). Surgical and non-surgical procedures to

treat fractures in hospitals constitute another large component of this outlay ($35 million,

11.5%).

11

Table 5: Direct health expenditure for osteoporosis, 2001-01 and 2004-05(62)

Health service area 2000-01 2004-05 Percent growth

Admitted patient services 31.8 m 35.0 m 10.1

Out-of-hospital medical services 29.4 m 47.3 m 60.8

Prescription pharmaceuticals 75.5 m 215.0 m 184.8

Research 2.6 m 7.0 m 169.2

Total 139.3 m 304.3 m 118.5 Source: AIHW 2009. AIHW Disease Expenditure Database

Effects of vitamin D on fractures

There are five published meta-analyses studies examining the effect of vitamin D, alone or in

combination with calcium on the reduction in the risk of hip fractures.(72-76)

The results of a

2009 systematic review and meta-analysis of postmenopausal women and men over 65 years

of age with involutional or post-menopausal osteoporosis found a statistically significant

reduction in the risk of hip fractures among those treated with a combination of vitamin D

and calcium, versus control.(73)

The authors concluded that there was an indication that

vitamin D3 doses between 400 IU and 800 IU plus 1,000 mg of calcium daily result in a

decreased risk of hip fractures.(73)

These results were corroborated by four other meta-

analyses in the same age group.(72, 74-76)

Two meta-analyses did not find a statistically

significant effect of vitamin D alone on hip or non-vertebral fractures, however completing

the studies with calcium and vitamin D was stated to be a confounding factor..(72, 73)

An

attempt was made in one of the meta-analyses to evaluate the effect of vitamin D in the

prevention of osteoporosis in younger women (19-49 years old) but no RCTs conducted

among this age group could be identified.(72)

Effect of vitamin D on falls

There are several systematic reviews and meta-analysis reporting that circulating 25-(OH)D

levels < 60–75 nmol/L have been associated with lower-extremity muscle weakness and

impaired balance, and accelerated losses in muscle mass, strength and physical function.(41, 77)

A minimum serum 25-(OH)D level of 60 nmol/L is required to effectively reduce the rate of

falls.(78)

Most evidence indicates that vitamin D (at daily doses of > 800 IU) needs to be

combined with adequate calcium (> 1000 mg/day) to reduce the risk of falls (and fractures).

Therefore, older people would be recommended to maintain adequate vitamin D and calcium

levels to reduce risk of falls.

Annual megadoses of vitamin D are not recommended. A large RCT in older Australian

women found that a single annual dose of 500,000 IU vitamin D3 for three to five (3–5) years

resulted in a 15% increase in falls and 26% increase in fractures. The increased risk of falls

was pronounced in the first three months after taking the dose and three-month post-dose

period, when serum 25-(OH)D levels would have been highest.(79)

Vitamin D and other diseases

A wide range of diseases have been associated with low levels of circulating serum 25-

(OH)D, including cardiovascular (80)

, diabetes,(81, 82)

some cancers,(83, 84)

autoimmune

disease(85)

and some neurological and mental health conditions (86)

including

schizophrenia(87)

. Three RCTs (83, 88, 89)

and two cohort studies (90, 91)

evaluated the effects of

vitamin D (with or without calcium) on cancer incidence or cancer mortality risk with a mean

follow-up of four to seven years. However, many of the studies were observational and their

results were inconsistent. Accordingly, proposals that recommend serum 25-(OH)D levels of

12

75–80 nmol/L or higher, and which serve as a protective factor that prevents the development

of diabetes and other diseases are not supported by a significant amount of data from

RCTs.(20)

There are however a few reports that identify vitamin D deficiency as a risk factor

to the development of type 2 diabetes. One recent Australian study reported that lower

25(OH)D concentrations were associated with increased Metabolic Syndrome1 risk and

higher waist circumference, serum triglyceride, fasting glucose, and insulin resistance.(81)

Another Australian study that evaluated the association between serum 25-(OH)D on five-

year incidence of diabetes and insulin sensitivity reported that higher serum 25-(OH)D levels

were associated with significantly reduced risk of diabetes in adult men and women.(82)

Service providers claiming MBS benefits for vitamin D testing

Most pathology in Australia is provided in comprehensive laboratories that provide a wide

range of testing services at a single location. Only approved pathology practitioners are

eligible to claim MBS items for vitamin D testing.

Previous assessment of vitamin D testing

One of the two health technology assessments (HTA) identified in the literature reviewed the

clinical utility of vitamin D testing performed by the Ontario Health Technology Advisory

Committee (OHTAC) in 2010.(92)

The assessment was initiated due to the increased volume

of laboratory vitamin D tests from 2004 to 2009 in Canada. The purpose of the assessment

was to evaluate the clinical utility of vitamin D testing, with specific reference to the

prevalence rates of vitamin D deficiency in both the general population and in patients with

kidney disease. The assessment focused primarily on bone health. It was noted that the use

of vitamin D with or without calcium has been shown to reduce the risk of fractures and falls

in elderly men and postmenopausal women. With respect to non-bone related health this

HTA concluded that as of August of 2009 there were insufficient data to support a link

between vitamin D and different non-bone health outcomes such as cancer, all-cause

mortality and some cardiovascular outcomes. OHTAC recommended that routine testing of

vitamin D levels should be endorsed for patients with certain bone related conditions, renal

disease or malabsorption syndromes and not the general population.

The second HTA reviewing vitamin D screening and testing prepared by Hayes Inc. for

Washington State Health Care Authority, HTA program published in November 2012 (93)

concluded that higher serum 25-(OH)D levels have a protective association with bone health,

but evidence to date has not demonstrated an association with health outcomes such as

fractures or falls. There was also very little evidence that healthy vitamin D levels in younger

adults protected this population group from the development of osteoporosis later in life.

With respect to non-bone related health, this HTA concluded that higher levels of serum 25-

(OH)D may protect adults against cardiovascular disease (CVD), type 2 diabetes, colorectal

cancer, ovarian cancer, and all-cause mortality. However, there was insufficient evidence

regarding a link between high serum vitamin D levels and with the reduced risk of obesity,

gestational diabetes or multiple sclerosis (MS). The assessment concluded that the literature

does not provide direct evidence that vitamin D screening in healthy populations as well as

patients with chronic disease improves health outcomes.

1 Metabolic Syndrome is defined as a combination of medical disorders that when occuring together increase the

risk of developing cardiovascular disease and type 2 diabetes.

13

Clinical Flow Chart

The clinical decision pathway which determines whether vitamin D testing should be

undertaken is provided in Figure 2.

Figure 2: Clinical flow chart for vitamin D testing

Patient presents to General Practitioner

Does the patient have any of the following clinical symptoms of

vitamin D deficiency?

• Widespread bone pain or tenderness

• Nonspecific myalgia

• Myalgia on strain

• Proximal muscle weakness

• Non-stress fracture

• Stress fracture e.g. femoral neck, scapula, ribs or vertebrae

• Rickets

• Low serum calcium or high Alkaline Phosphatase

• Low serum phosphate

• Low bone density on DEXA or osteopenia on x ray

No

Does the patient have any of the following risk factors associated with

vitamin D deficiency?

• Housebound or in residential aged care facility

• Patients >65

• Indoor worker

• Long sleeve clothing, staying in the shade

• Dark skinned

• Vegetarians

• Diabetes

• Renal/liver disease

• Pregnancy or breast feeding

• Gastrointestinal disorders e.g. Crohn’s, Coeliac, gastrectomy

• Obesity

No YesYes

Is Vitamin D testing medically

necessary?


necessary?

No


necessary?

No MBS claim for vitamin

D testing

Measure serum Vitamin D

Claim MBS item numbers

66608 or 66609

YesNo


D testing

No


D testing

Measure serum Vitamin D

Claim MBS item numbers

66608 or 66609

Yes

14

METHODOLOGY

The review will be primarily based on a fit-for-purpose, evidence based methodology. Fit-

for-purpose in this context means that where comprehensive, high quality literature is found

which clearly addresses the clinical questions, less work will be undertaken to find and

analyse lower quality evidence or grey papers. The less comprehensive or lower quality the

evidence relating to a clinical question (or where the evidence is not directly comparable to

the Australian context), more work will be undertaken in finding and analysing lower quality

evidence to ensure robust findings.

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 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. RCC, 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 (94)

are used to develop

well-defined questions for this 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

15

within which the literature will be sourced, and language restrictions as discussed above and

in appendix C). The PICO for the review of vitamin D testing are shown in Table 6.

Table 6: Clinical and research questions for the vitamin D testing items under review Population Intervention Comparator Outcomes

(1) General health population

(includes pregnant women,

elderly, dark-skinned people,

indoor workers etc.)

Serum vitamin D testing Supplementation

Safety

Complications associated with

Vitamin D testing (e.g. infection, needle injuries)

Effectiveness

Physical health outcome as a

consequence of the vitamin

D testing (e.g. all-cause

mortality, anaemia, NTDs,

CVD, neuropathy,

depression, dementia)

(2) Patients diagnosed with

osteoporosis and osteomalacia

(3) Children with rickets

(4) Patients with chronic disease

(kidney disease, multiple

sclerosis, diabetes, CVD

disease, gastrointestinal and

malabsorption disorders etc.)

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 D 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, and reviews relevant to the review of vitamin D 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 D testing?

(2) What is the effectiveness of vitamin D testing in improving outcomes in each target

population?

(3) What are the safety and quality implications (including morbidity, mortality and patient

satisfaction) associated with vitamin D testing in each target population?

(4) How do safety and quality outcomes of vitamin D testing vary according to:

a. the difference in testing methodologies?

b. frequency of testing?

(5) What is the evidence regarding the cost implications associated with vitamin D testing

services in each target population?

16

MBS data

MBS data are available for MBS item numbers 66608 and 66609 since the early 1990s. A

brief review of the available MBS data for the purposes of drafting the Vitamin D Testing

Protocol identified an overall increase in claims for vitamin D testing, particularly for item

number 66608. 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 66608 and 66609?

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 D testing?

d. Are the Medicare claims data consistent with trends in the incidence/prevalence of the

conditions/diseases being addressed by the services?

e. Are there other pathology tests claimed in association with vitamin D testing?

Guideline concordance

An analysis of the two vitamin D 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) Are the existing MBS item for services (66608 and 66609), including the associated

explanatory notes appropriate?

a. Is the descriptor for the MBS item number/service under review 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 D testing in

each target population across the patient journey?

(2) Is the current fee structure for the items under review appropriate?

17

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88. Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O'Sullivan MJ, et al. Calcium

plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med. 2006 Feb

16;354(7):684-96.

89. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation

on fractures and mortality in men and women living in the community: randomised double blind

controlled trial. Bmj. 2003 Mar 1;326(7387):469.

90. Freedman DM, Looker AC, Chang SC, Graubard BI. Prospective study of serum vitamin D and cancer

mortality in the United States. J Natl Cancer Inst. 2007 Nov 7;99(21):1594-602.

91. Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the

general population. Arch Intern Med. 2008 Aug 11;168(15):1629-37.

92. Clinical utility of vitamin d testing: an evidence-based analysis. Ont Health Technol Assess Ser.

2010;10(2):1-93.

93. Inc H. Vitamin D Screening and Testing: Washington State Health Care Authority2012.

94. 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.

95. 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.

96. 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.

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

21

APPENDIX A – MBS DATA

The MBS item numbers relevant to vitamin D testing

Table A.1 shows the two in-scope MBS item number for vitamin D testing.

Table A.1: Description of vitamin D testing funded under the MBS

Item Number MBS Item Number description

66608 Vitamin D or D fractions (Schedule fee: $42.55)

66609 A test described in item 66608 if rendered by a receiving Approved Pathology Practitioner

(APP) - 1 or more tests (Item is subject to rule 18) (Schedule Fee: $42.55)

Description of Rule 18: The term "Episode Cone" describes an arrangement under which Medicare benefits

payable in a patient episode for a set of pathology services, containing more than three items, ordered by a

general practitioner for a non-hospitalised patient, will be equivalent to the sum of the benefits for the three items

with the highest Schedule fees. Item 66609 is not included in the count of the items performed when applying

the episode cone Source: Department of Human Services Medicare

MBS usage and expenditure

Table A.2 shows that the volume of vitamin D tests performed in Australia has steadily

increased over the past ten years, from 73,330 tests in 2002 to more than three million tests in

2012 (nearly up 4,600%). The annual number of claims for MBS item number 66609 has

been variable since May 2007.

Table A.2: Number of claims for Vitamin D testing MBS items since 2000/2001

MBS item

no

Financial year

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

66608 73,330 117,474 171,288 249,933 445,854 847,029 1,492,904 2,219,553 2,982,658 3,481,966

66609 743 13,329 9,442 11,397 15,414 7,203

Total 73,330 117,474 171,288 249,933 446,597 860,358 1,502,346 2,230,950 2,998,072 3,489,169

Source: Department of Human Services Medicare

The pattern of use for item number 66608 is further analysed in Figure A.1 showing different

patterns of usage by age, gender and time period. This analysis shows that vitamin D testing

claimed under MBS item number 66608 is performed for both genders. However, the

number of claims for vitamin D testing is particularly significant for females aged between 24

and 84, showing a marked increase from 2008 to 2012 (green line) compared to 2004-2008

(red line) and 2000 to 2004 (blue line).

22

Figure A.1: Usage of MBS item 66608 by age and gender since 2000

0

1,000,000

0-4

5-1

4

15-

24

25-

34

35-

44

45-

54

55-

64

65-

74

75-

84

85+

No

of M

BS

cla

ims

Males

00-04 04-08 08-12

0

200,000

400,000

600,000

800,000

1,000,000

1,200,000

1,400,000

1,600,000

0-4 5-14 15-24 25-34 35-44 45-54 55-64 65-74 75-84 85+

No o

f M

BS

cla

ims

Females

00-04 04-08 08-12

Figure A.2 shows that the annual MBS benefits paid for vitamin D testing (item numbers

66608 and 66609) has increased significantly from $2.6 million in 2002 to $126.5 million in

2012. The significant increase in the benefits paid for both item numbers is consistent with

the increase in the volume of claims.

Figure A.2: Benefits paid for MBS item number 66608 and 66609 since 2002/2003

Source: Department of Human Services Medicare

No

. o

f M

BS

cla

ims

66608 66609

23

APPENDIX B - SEARCH TERM STRATEGY

Clinical questions

1. What is the safety and effectiveness of vitamin D testing?

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

Population Search Terms

1. Healthy population Embase and Medline Population – (‘preeclampsia ’/exp OR ‘preeclampsia’ OR ‘pregnancy’/exp OR

‘pregnancy’ OR ‘infant’/exp OR ‘infant’ OR ‘human milk’/exp OR ‘human

milk’ OR ‘lactation’/exp OR ‘lactation’ OR ‘dark skin’/exp OR ‘dark skin’ OR

‘obesity’/exp OR ‘obesity’ OR ‘elderly’/exp OR ‘elderly’ OR ‘aged’/exp OR

‘aged’ OR ‘indoor workers’)

AND

Intervention – (Vit*D OR ‘vitamin D’/exp OR’ vitamin D’ OR 25-OHD OR

25OHD3 OR 25(OH)D3 OR 25-OHD3 OR 25-(OH)D3 OR ‘25-hydroxyvitamin

D’/exp OR ‘25-hydroxyvitamin D’ OR ‘25-hydroxycholecalciferol’/exp OR ‘25-

hydroxycholecalciferol’ OR ‘25-hydroxyergocalciferol’/exp OR ‘25-

hydroxyergocalciferol’ OR ‘calcidiol’/exp OR ‘calcidiol’ OR

‘cholecalciferol’/exp OR ‘cholecalciferol’ OR ‘ergocalciferol’/exp OR

‘ergocalciferol’) AND (‘testing’/exp OR ‘testing’ OR ‘haematologic test*’/exp

OR ‘haematologic test*’)

AND

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

Cochrane Population – ((MeSH descriptor Preeclampsia explode all trees) OR (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 Obesity explode all

trees) OR (MeSH descriptor Aged explore all trees) OR ((preeclampsia) OR

(preeclampsia):ti,ab,kw) 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 ((dark skin) OR (dark skin):ti,ab,kw) OR

((obesity) OR (obesity):ti,ab,kw) OR ((indoor worker) OR (indoor

worker):ti,ab,kw))

AND

Intervention – ((MeSH descriptor Vitamin D explode all trees) OR (Vitamin

D):ti,ab,kw OR (MeSH descriptor 25-OHD explode all trees) OR (25-

OHD):ti,ab,kw OR (MeSH descriptor 25OHD3 explode all trees) OR

(25OHD3):ti,ab,kw OR (MeSH descriptor 25(OH)D3 explode all trees) OR

(25(OH)D3):ti,ab,kw OR (MeSH descriptor 25-OHD3 explode all trees) OR (25-

OHD3):ti,ab,kw OR (MeSH descriptor 25-(OH)D3 explode all trees) OR (25-

(OH)D3):ti,ab,kw OR (MeSH descriptor 25-Hydroxyvitamin D explode all trees)

OR (25-Hydroxyvitamin D):ti,ab,kw OR (MeSH descriptor 25-

Hydroxycholecalciferol explode all trees) OR (25-

Hydroxycholecalciferol):ti,ab,kw OR (MeSH descriptor 25-

Hydroxyergocalciferol explode all trees) OR (25-Hydroxyergocalciferol):ti,ab,kw

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

(MeSH descriptor Cholecalciferol explode all trees) OR

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

OR (Ergocalciferol):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

24


2. Patients diagnosed

with osteoporosis and

osteomalacia

Embase and Medline Population – (‘osteoporosis’/exp OR ‘osteoporosis’ OR ‘osteomalacia’/exp OR

‘osteomalacia’ OR ‘bone density’/exp OR ‘bone density’ OR ‘bone’/exp OR

‘bone’ OR ‘fractures’/exp OR ‘fractures’ OR ‘falls’/exp OR ‘falls’ OR

osteoporo* OR osteomalac*)

AND









AND


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

descriptor Osteomalacia explode all trees) OR (MeSH descriptor Bone density

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

descriptor Fractures explode all trees) OR (MeSH descriptor Falls explode all

trees) OR ((osteoporosis) OR (osteoporosis):ti,ab,kw) OR ((osteomalacia) OR

(osteomalacia):ti,ab,kw) OR ((bone density) OR (bone density):ti,ab,kw) OR

((bone) OR (bone):ti,ab,kw) OR ((fractures) OR (fractures):ti,ab,kw) OR ((falls)

OR (falls):ti,ab,kw) OR osteoporo* OR osteomalac*)

AND


















AND


3. Children diagnosed

with rickets

Embase and Medline Population – ((‘rickets’/exp OR ‘rickets’) OR (‘rachitis’/exp OR ‘rachitis’) OR

(‘bone development’/exp OR ‘bone development’))

AND









AND

25



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

rachitis explode all trees) OR (MeSH descriptor Bone Development explode all

trees) OR((rickets) OR (rickets):ti,ab,kw) OR ((rachitis) OR (rachitis):ti,ab,kw)

OR ((bone development) OR (bone development):ti,ab,kw))

AND


















AND


26


4. Patients with chronic

disease

Embase and Medline Population – ((‘cardiovascular disease’/exp OR ‘cardiovascular disease’) OR

(‘heart disease’/exp OR ‘heart disease’) OR (‘ coronary disease’/exp OR

‘coronary disease’) OR ‘myocardial infarct*’ OR (‘stroke’/exp OR ‘stroke’) OR

(‘ischemia’/exp OR ‘ischemia’) OR ‘pulmonary embol*’ OR ‘embol*’ OR

(‘heart failure’/exp OR ‘heart failure’) OR (‘peripheral vascular disease’/exp OR

‘peripheral vascular disease’) OR (‘kidney disease’/exp OR ‘kidney disease’)

OR (‘diabetes mellitus’/exp OR ‘diabetes mellitus’) OR (‘rheumatoid

arthritis’/exp OR ‘rheumatoid arthritis’) OR (‘multiple sclerosis’/exp OR

‘multiple sclerosis’) OR (‘breast cancer’/exp OR ‘breast cancer’) OR (‘prostate

cancer’/exp OR ‘prostate cancer’) OR (‘inflammatory bowel disease’/exp OR

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

OR (‘ulcerative colitis’/exp OR ‘ulcerative colitis’))

AND









AND


Cochrane Population – ((MeSH descriptor Cardiovascular Disease explode all trees) OR

(MeSH descriptor Heart Disease explode all trees) OR (MeSH descriptor

Coronary Disease explode all trees) OR (MeSH descriptor Myocardial Infarction

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

descriptor Ischemia explode all trees) OR (MeSH descriptor Pulmonary

Embolism explode all trees) OR (MeSH descriptor Heart Failure explode all

trees) OR (MeSH descriptor Peripheral Vascular Disease explode all trees) OR

(MeSH descriptor Kidney Disease explode all trees) OR (MeSH descriptor

Diabetes Mellitus explode all trees) OR (MeSH descriptor Rheumatoid Arthritis

explode all trees) OR (MeSH descriptor Multiple Sclerosis explode all trees) OR

(MeSH descriptor Breast Cancer explode all trees) OR (MeSH descriptor Prostate

Cancer explode all trees) OR (MeSH descriptor Inflammatory Bowel Disease

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

(MeSH descriptor ulcerative colitis explode all trees) OR (Cardiovascular

disease) OR (cardiovascular disease):ti,ab,kw OR (heart disease) OR (heart

disease):ti,ab,kw OR (coronary disease) OR (coronary disease):ti,ab,kw OR

(myocardial infarction) OR (myocardial infarction):ti,ab,kw OR (stroke) OR

(stroke):ti,ab,kw OR (ischemia) OR (ischemia):ti,ab,kw OR (heart failure) OR

(heart failure):ti,ab,kw OR (peripheral vascular disease) OR (peripheral vascular

disease):ti,ab,kw OR (kidney disease) OR (kidney disease):ti,ab,kw OR (diabetes

mellitus) OR (diabetes mellitus):ti,ab,kw OR (rheumatoid arthritis) OR

(rheumatoid arthritis):ti,ab,kw OR (multiple sclerosis) OR (multiple

sclerosis):ti,ab,kw OR (breast cancer) OR (breast cancer):ti,ab,kw OR (prostate

cancer) OR (prostate cancer):ti,ab,kw OR (inflammatory bowel disease) OR

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

disease):ti,ab,kw OR (ulcerative colitis) OR (ulcerative colitis):ti,ab,kw)

AND







27













AND


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

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


1. Patients undertaking

serum vitamin D testing Embase and Medline Intervention – (Vit*D OR ‘vitamin D’/exp OR ’vitamin D’ OR 25-OHD OR

25OHD3 OR 25(OH)D3 OR 25-OHD3 OR 25-(OH)D3 OR ‘25-

hydroxyvitamin D’/exp OR ‘25-hydroxyvitamin D’ OR ‘25-

hydroxycholecalciferol’/exp OR ‘25-hydroxycholecalciferol’ OR ‘25-

hydroxyergocalciferol’/exp OR ‘25-hydroxyergocalciferol’ OR ‘calcidiol’/exp

OR ‘calcidiol’ OR ‘cholecalciferol’/exp OR ‘cholecalciferol’ OR

‘ergocalciferol’/exp OR ‘ergocalciferol’) 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 D explode all trees) OR (Vitamin




(25(OH)D3):ti,ab,kw OR (MeSH descriptor 25-OHD3 explode all trees) OR

(25-OHD3):ti,ab,kw OR (MeSH descriptor 25-(OH)D3 explode all trees) OR

(25-(OH)D3):ti,ab,kw OR (MeSH descriptor 25-Hydroxyvitamin D explode all

trees) OR (25-Hydroxyvitamin D):ti,ab,kw OR (MeSH descriptor 25-



Hydroxyergocalciferol explode all trees) OR (25-

Hydroxyergocalciferol):ti,ab,kw OR (MeSH descriptor Calcidiol explode all

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

trees) OR (Cholecalciferol):ti,ab,kw OR (MeSH descriptor Ergocalciferol

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

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

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

AND

Economic Terms – (((economic aspect) OR (economic aspect):kw) OR ((cost

benefit) OR (cost benefit):kw)) OR ((cost effectiveness) OR (cost

effectiveness):kw) OR (MeSH descriptor Cost-Benefit Analysis explode all

trees) OR (MeSH descriptor Costs and Cost Analysis explode all trees))

AND


28

APPENDIX C – SEARCH STRATEGY CRITERIA

Search strategies generally include a combination of indexing terms (e.g. MeSH or Emtree

headings) and text word terms. Tables C.1 and C.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 Vitamin D testing

Comparator No vitamin D 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.

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.

29

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.(95)

Study

quality will be evaluated and reported using the NHMRC Quality Criteria (Table C.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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