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Proposal form for the evaluation of a genetic test for NHS ServiceGene Dossier/Additional Provider

This form has been developed as a tool to evaluate genetic tests and should be submitted to the UKGTN Project team. This form should only be submitted for tests that will be offered on a national basis.

ADMINISTRATIVE DETAILS If electronic signatures are not available please post this page to

UKGTNEvaluation number #

Disorder(s)/condition(s)

Gene(s)

Type of application Gene Dossier Additional Provider

Date of submission

Provider Laboratory

Name of Laboratory Director/Head of Laboratory

Print Signature Date

Name of Person Completing Dossier


Position

Address

Telephone Number

Fax

E-Mail Address

Name, email & postal address of clinical co-applicant/collaborator


Email address:Postal address:

Name & email address of lead genetic NHS commissioner

Name & email address of NHS commissioner of other major referring specialty (if applicable)

Is this part of a highly specialised service (HSS - formerly NSCT/NCG)? Yes No Don’t know

If yes:a) Please name the highly specialised service:

b) Is this to be incorporated into a service that is already funded nationally? Yes No

Copyright UKGTN © 2013 1

For completion by UKGTN administration

Date of receipt

Date of resubmission to GTEWG* (if applicable)

Date of submission for Chair’s action (if applicable)

Date of receipt of gene dossier returned to Project Team following initial evaluation through the rare gene dossier process

Date of receipt of GD if GD is approved subject to agreement to minor amendments or following submission of additional informationProject Team decision for additional providers that do not need to go to the full working group (i.e. where testing criteria is already published and agreed to by the submitting lab)

Date Decision

Project Team decision to the GTEWG following evaluation through the Rare Gene Dossier Process

Date Decision

Final decision of UKGTN GTEWG / Chair

Date Decision

Project Team decision if GD is approved subject to agreement to minor amendments or following submission of additional information

Date Decision

*GTEWG: Genetic Test Evaluation Working Group (previously Gene Dossier Working Group)

HOW TO COMPLETE THE FORM

Should I complete this form as a full Gene Dossier or an Additional Provider? Before completing this form please check the NHS Directory of Genetic Testing

(http://www.ukgtn.nhs.uk/gtn/UKGTN-information/directory-and-associated-pages.html) or online database to see if the test is already available through the network. If the test is already available then you need only complete this form as an Additional Provider.

If the test (disorder/gene combinations ) that you wish to provide has previously been approved, please use this form as an ADDITIONAL PROVIDER APPLICATION and you need only


http://www.ukgtn.nhs.uk/gtn/UKGTN-information/directory-and-associated-pages.html

complete questions highlighted in orange (i.e. 1-15, 18, 22, 24, 27 and 33 if you disagree to current Testing Criteria, and the website proforma).

Who can submit a Gene Dossier/Additional Provider? The application must be submitted by the Director of a UKGTN laboratory and should be

completed in collaboration with clinical and research colleagues where appropriate. The laboratory should take ownership of the submission and UKGTN will correspond with the Director of the laboratory.

The test involves more than one disorder/gene – how many forms should I complete? Forms should be completed for each single inherited condition (e.g. isolated Fallot’s Tetralogy)

with single or multiple genes. If there is more than one disorder ASSOCIATED WITH THE GENE(S) but the disorders have different clinical presentations, please submit these as separate forms, per disorder. A single form should be submitted if the specific test for a disorder is defined as the analysis of more than one gene e.g. BRCA 1 & 2. If there is more than one disorder ASSOCIATED WITH THE GENE(S) and the disorders have clinical presentations with significant clinical overlap, it may be possible to submit one form for these disorders/genes. If you are unsure whether or not to submit one form or a number of forms, please contact the UKGTN project team who will seek advice from the UKGTN clinical and scientific advisors. The application will be evaluated in the context of the use of the test in a particular disorder and in a specified population.

Administration Please submit this form electronically Word format, using font Arial, size 11 and black text

throughout. If you are unable to provide electronic signatures for page 1, please arrange for the form to be

signed and post only page 1 to the UKGTN team.

Further information on the completion of this form may be obtained from the UKGTN Project team,Tel: 020 7932 3969, email: [email protected]

Prior to UKGTN approval the UKGTN Commissioning Support working group may request further information from the applicants on any significant downstream funding implications.

Please note that completed Gene Dossiers minus the administration and financial details will be posted on the UKGTN website.

To propose a test for consideration for possible inclusion in the NHS Directory of Genetic Testing in the year 2015-2016, this form must be submitted by 31st January 2014.

Gene Dossiers: may be submitted all year round. In order for a Gene Dossier to be evaluated for the commissioning cycle of the following year it must be submitted by January 31st of the preceding year. Please note that additional information is often requested after an initial application therefore early submission is recommended.

Additional providers: do not have a deadline for submission but will be evaluated throughout the year although Gene Dossiers will take priority.

Please return the form to: UK Genetic Testing Network Email: [email protected]/o NHS LondonNational Specialised Commissioning Team2nd Floor, Southside105 Victoria St London SW1E 6QT


mailto:[email protected]

Evaluation number: #

TEST – DISORDER/CONDITION – POPULATION TRIADSubmitting laboratory: Approved:1. Disorder/condition – approved name and symbol as published on the OMIM database (alternative names will be listed on the UKGTN website)

If this submission is for a panel test please complete appendix 1 listing all of the conditions included using approved OMIM name, symbol and OMIM number.

2. OMIM number for disorder/condition If a panel test – see 1. above

3a. Disorder/condition – please provide, in laymen’s terms, a brief (2-5 sentences) description of how the disorder(s) affect individuals and prognosis.3b Disorder/condition – if required please expand on the description of the disorder provided in answer to Q3a.4. Disorder/condition – mode of inheritance5. Gene – approved name(s) and symbol as published on HGNC database (alternative names will be listed on the UKGTN website)

If this submission is for a panel test please complete appendix 2 listing all of the genes included using approved HGNC name, symbol, number and OMIM number.

6a. OMIM number for gene(s) If a panel test – see 5. above

6b HGNC number for gene(s) If a panel test – see 5. above

7a. Gene – description(s)

7b. Number of amplicons to provide this test (molecular) or type of test (cytogenetic)7c. GenU band that this test is assigned to for index case testing8. Mutational spectrum for which you test including details of known common mutations9a. Technical method(s)

9b If a panel test using NGS please state if it is a conventional panel or a targeted exome test.9c. Panel/targeted exome Testsi) Do the genes have 100% coverage? If not what is the strategy for dealing with the gaps in coverage?ii) Does the test include MLPA?iii) Does this use sanger sequencing or Next Generation Sequencing (NGS)?iv) If NGS is used, does the lab adhere to the Practice Guidelines for NGS?

Copyright UKGTN © 2012-2013 4


10 Is the assay to be provided by the lab or is it to be outsourced to another provider?If to be outsourced, please provide the name of the laboratory.11. Validation process Please explain how this test has been validated for use in your laboratory or submit your internal validation documentation

12a. Are you providing this test already? No Yes12b. If yes, how many reports have you produced? Please provide the time period in which these reports have been produced and whether in a research or a full clinical diagnostic setting.12c. Number of reports mutation positive12d. Number of reports mutation negative13. For how long have you been providing this service?14a. Is there specialised local clinical/research expertise for this disorder?

No Yes

14b. If yes, please provide details15. Are you testing for other genes/disorders/conditions closely allied to this one? Please give details

16. Based on experience what will be the national (UK wide) activity, per annum, for: 16a. Index cases16b. Family members where mutation is known17a. Does the laboratory have capacity to provide the expected national activity?

17b. If your laboratory does not have capacity to provide the full national need please could you provide information on how the national requirement may be met. For example, are you aware of any other labs (UKGTN members or otherwise) offering this test to NHS patients on a local area basis only? This question has been included in order to gauge if there could be any issues in equity of access for NHS patients. It is appreciated that some laboratories may not be able to answer this question. If this is the case please write “unknown”.

18. Please justify the requirement for another laboratory to provide this test e.g. insufficient national capacity.



EPIDEMIOLOGY19a. Estimated prevalence of condition in the general UK population 19b. Estimated incidence of condition in the general UK populationPlease identify the information on which this is based

20. Estimated gene frequency (Carrier frequency or allele frequency)Please identify the information on which this is based

21. Estimated penetrance Please identify the information on which this is based

22. Estimated prevalence of condition in the population of people that meet the Testing Criteria.INTENDED USE (Please use the questions in Annex A to inform your answers)23. Please tick either yes or no for each clinical purpose listed.Panel Tests: a panel test would not be used for pre symptomatic testing, carrier testing and pre natal testing as the familial mutation would already be known in this case and the full panel would not be required. Diagnosis Yes No Treatment Yes No Prognosis & management Yes No Presymptomatic testing (n/a for panel tests) Yes No Carrier testing for family members (n/a for panel tests) Yes No Prenatal testing (n/a for panel tests) Yes No TEST CHARACTERISTICS24. Analytical sensitivity and specificityThis should be based on your own laboratory data for the specific test being applied for or the analytical sensitivity and specificity of the method/technique to be used in the case of a test yet to be set up.

25. Clinical sensitivity and specificity of test in target populationThe clinical sensitivity of a test is the probability of a positive test result when condition is known to be present; the clinical specificity is the probability of a negative test result when disorder is known to be absent. The denominator in this case is the number with the disorder (for sensitivity) or the number without condition (for specificity).

26. Clinical validity (positive and negative predictive value in the target population)The clinical validity of a genetic test is a measure of how well the test predicts the presence or absence of the phenotype, clinical condition or predisposition. It is measured by its positive predictive value (the probability of getting the condition given a positive test) and negative predictive value (the probability of not getting the condition given a negative test).



27. Testing pathway for tests where more than one gene is to be testedPlease include your testing strategy if more than one gene will be tested and data on the expected proportions of positive results for each part of the process. Please illustrate this with a flow diagram. This will be added to the published Testing Criteria.

CLINICAL UTILITY28. How will the test change the management of the patient and/or alter clinical outcome?

29. Benefits of the test for the patient & other family membersPlease provide a summary of the overall benefits of this test.

30. What will be the consequences for patients and family members if this test is not approved?

31. Is there an alternative means of diagnosis or prediction that does not involve molecular diagnosis? If so (and in particular if there is a biochemical test), please state the added advantage of the molecular test.

32. Please describe any specific ethical, legal or social issues with this particular test.

33. Only complete this question if there is previously approved Testing Criteria and you do not agree with it. Please provide revised Testing Criteria on the Testing Criteria form and explain here the changes and the reasons for the changes.

34. List the diagnostic tests/procedures that an index case no longer needs if this genetic test is available.

Type of test Cost (£)Costs and type of imaging proceduresCosts and types of laboratory pathology tests (other than molecular/cyto genetic test proposed in this gene dossier)Costs and types of physiological tests (e.g. ECG)Cost and types of other investigations/procedures (e.g. biopsy)Total cost tests/procedures no longer required

35. Based on the expected annual activity of index cases (Q15a), please calculate the estimated annual savings/investments based on information provided in Q33.


Number of index cases expected annually (a)Cost to provide tests for index cases if the genetic test in this gene dossier was not available (see Q34)

(b)

Total annual costs pre genetic test (a) x (b) = (c)Total annual costs to provide genetic test (a) x cost of genetic testing for index case = (d)Total savings/investment (c) – (d)


36. REAL LIFE CASE STUDY In collaboration with the clinical lead, describe TWO real case examples:

1. prior to availability of genetic test2. post availability of genetic test

to illustrate how the test improves patient experience and the costs involved.

Case example one – pre genetic test

Please provide narrative here and expand box to accommodate the text.

PRE GENETIC TEST COSTSType of test Cost

Costs and type of imaging proceduresCosts and type of laboratory pathology tests Costs and type of physiological tests (e.g. ECG)Cost and type of other investigations/procedures (e.g. biopsy)Cost outpatient consultations (genetics and non genetics)Total cost pre genetic test £

Case example two – post genetic test

Please provide narrative here and expand box to accommodate the text.POST GENETIC TEST COSTS

Type of test CostCosts and type of imaging proceduresCosts and types laboratory pathology tests (other than molecular/cyto genetic proposed in this gene dosier)Cost of genetic test proposing in this gene dossierCosts and type of physiological tests (e.g. ECG)Cost and type of other investigations/procedures (e.g. biopsy)Cost outpatient consultations (genetics and non genetics)Total cost post genetic test £

37. Estimated savings between two case examples described £



If testing criteria is already published, please do not complete this section unless you disagree with the current content. If your testing criteria differs from the current testing criteria, please advise the scientific advisor in advance of submitting the application.(Please contact the UKGTN office if you are unsure whether testing criteria is available)

FinancialSECTION A

Price per test and expected national activity across all specialties

Expected activity per annum across

all specialties

Price per test Total (£)

These prices will be used to inform NHS commissioners of the estimated total annual funding required to provide this test

Index cases (see Q15a)

Family members

(see Q15b)

For this test please provide the estimated activity by specialty as per types of referrers on the Testing Criteria (where the Testing Criteria lists types of referrers from specialties outside of clinical genetics)

Specialty

NHS CB or CCG funded? (see note below*)

Index cases Family members

Clinical genetics NHS CB

*Other than for clinical genetics, you need to identify the relevant commissioner for referrals in England; either the NHS Commissioning Board (NHS CB) where the test will be ordered in relation to a prescribed service or from Clinical Commissioning Groups (CCG) in relation to non-prescribed services.

SECTION B

Expected start up date of service if approved YES NOIf this service is approved for inclusion on the NHS Directory of Genetic Testing, please confirm that the service will be available from April 2014.

If the service will not be available from April 2014, please advise expected start date.

Intellectual Property YES NOAre there any intellectual property issues related to this test?

In particular, are there UK licensing requirements for the provision of this test?

Please provide details of any issues identified

UKGTN Website information proforma – must be completedPlease indicate what service you propose to offer. This is the information that will be displayed on the UKGTN


UKGTN Testing CriteriaTest name: (for UKGTN administration to complete)

Approved name and symbol of disorder/condition(s):If a panel test please complete Testing Criteria appendix 1

OMIM number(s):

Approved name and symbol of gene(s):If a panel test please complete Testing Criteria appendix 2

OMIM number(s):

Patient name: Date of birth:

Patient postcode: NHS number:

Name of referrer:

Title/Position: Lab ID:

Referrals will only be accepted from one of the following:Note for completion: please list the types of referrers for appropriate requests for testing (e.g. consultant clinical geneticists, consultant paediatric neurologists etc).Referrer Tick if this refers to

you.

Minimum criteria required for testing to be appropriate as stated in the Gene Dossier:Note for completion: please insert the criteria for testing e.g. list clinical symptoms and other investigations that would be expected to have been carried out prior to the DNA test and the results required to make the referral appropriate. Please specify the relationship between criteria using keywords e.g. and, or, at least N of the following. Examples to help in the completion of this are available on the UKGTN website. The boxes can be expanded and rows can be added.Criteria Tick if this patient

meets criteria

At risk family members where familial mutation is known.(delete if not applicable)Additional Information:For panel tests: At risk family members where familial mutation is known do not require a full panel test but should be offered analysis of the known mutation (delete if the test is not a panel test)

If the sample does not fulfil the clinical criteria or you are not one of the specified types of referrer and you still feel that testing should be performed please contact the laboratory to

discuss testing of the sample.


website if your application is successfulLaboratoryName of gene dossierService levels Qualifiers Turnaround time

(Working days)Price (£) - Please state whether price is per gene or for all genes

Note Please provide any notes e.g. if price is per gene or per combination of genes

Sequencing of the entire coding region of a gene

Prenatal Diagnosis

Postnatal Diagnosis Routine

Postnatal Diagnosis Urgent

Sequencing of the entire coding region of a gene PLUS copy number analysis

Prenatal Diagnosis



Sequencing of selected exons

Prenatal Diagnosis



Mutation Scanning Prenatal Diagnosis



Targeted mutation analysis

Prenatal Diagnosis



Testing for known mutations in family members

Prenatal Diagnosis



Gene Tracking Prenatal Diagnosis



Targeted copy number analysis

Prenatal Diagnosis



Whole genome analysis for copy number imbalance

Prenatal Diagnosis



Chromosome analysis for balanced structural chromosome rearrangements

Prenatal Diagnosis



Chromosome instability (breakage) analysis

Prenatal Diagnosis



Non Invasive Pre Natal Diagnosis

Prenatal Diagnosis

Please tick the QA schemes that you undertake for this disorder/condition

UKNEQAS

EMQN

Generic Technical Scheme

No EQA scheme available

Not participating

Gene dossier feedback form



The feedback form will be completed by the UKGTN team and returned to the laboratory following evaluation of the dossier.Application number: #

Date of meeting

Question # Please advise if you agree to the amendments

Question # Please provide information as detailed in the gene dossier

Testing Criteria Please state if you agree to suggested amendments and if not please make changes on the Testing Criteria

Financial Information Please provide estimated activity split across the specialties that will be referring.

Website proforma

Other comments

Recommendation Approved

Approved subject to agreement to minor amendments and/or supply of additional information

Chairs action

Not approved

Project Team support recommendation to Genetic Test Evaluation Working Group

Project Team support recommendation to Genetic Test Evaluation Working Group following laboratory agreement to amendments and providing additional information.

Project Team require additional information and/or agreement to amendments and will review again prior to making decision whether or not to recommend to Genetic Test Evaluation Working Group

Project Team do not support and will recommend to Genetic Test Evaluation Working Group not to approve

Annex A

Clinical indications for Molecular Tests for Genetic Disorders



In clinical practice ordering molecular tests for genetic disorders may affect management in a number of areas –a. Diagnosisb. Treatmentc. Prognosis and Managementd. Presymptomatic diagnostic testinge. Genetic Risk assessment, includes carrier testing for family members and pre natal testing

Most current molecular genetic tests will be useful for only a subset of these. It may be helpful in completing the gene dossier to consider which of these clinical management areas the test is likely to enhance. These will be considered by the panel in the evaluation of the proposed test. The following questions under each of these headings may help in the preparation of the gene dossier.

a) Diagnosis

- Can a diagnosis be made for certain by any other method including clinical examination by an expert?- Will a molecular diagnosis remove the need to do other expensive or invasive tests?

b) Treatment

- Will a specific molecular diagnosis affect treatment?

c) Prognosis and Management

- Is there evidence in this disorder that a specific molecular sub-type will affect prognosis and management to a significant extent? In other words - will the result significantly affect the lifestyle choices of the patient or the family?

d) Presymptomatic Diagnostic Screening

- Will a positive molecular result accurately predict future disorder and alter management? - Will a negative molecular result be definitive (i.e. further tests do not need to be carried out)?

e) Genetic Risk Assessment

- Will molecular diagnosis in the affected person reduce the need for other clinical tests in the rest of the family? - Will molecular diagnosis resolve the mode of inheritance? (e.g. HMSN) - Will molecular diagnosis provide a means of pre-natal diagnosis or carrier detection?- Will molecular diagnosis allow pre-symptomatic testing for other family members?

Notes

The clinical validity of a genetic test is a measure of how well the test predicts the presence or absence of the phenotype, clinical disorder or predisposition. It is measured by its positive predictive value (the probability of getting the disorder given a positive test) and negative predictive value (the probability of not getting the disorder given a negative test). The denominator in this case is the number of people with a positive or a negative test respectively - not the number with or without the disorder. The clinical validity may be calculated knowing the sensitivity and the specificity and the prevalence of the disorder in the population being studied. Positive and negative predictive values depend critically on the prevalence of the disorder in the test population

Positive predictive value and penetrance are notionally equivalent for any single genetic allele – the probability of developing disorder given a positive test. The relationship is much more complex if more than one gene is responsible for the disorder (locus heterogeneity), or if in any one gene there are multiple alleles (allelic heterogeneity), unless all the alleles are tested. In these cases, there are implications for the clinical sensitivity of the test and for its negative predictive value. For example, for a disorder (such as APKD) that may be



caused by either of two separate genes, even if each is 100 percent penetrant, the clinical sensitivity and the negative predictive value (and clinical validity) will both be reduced: clinical sensitivity since its maximum value can be no greater than the proportion of the disorder that is caused by that particular gene, and negative predictive value since a negative test on Gene A will be no guarantee that the patient will not develop the phenotype, because the disorder may be caused by Gene B. A similar form of analysis may be applied to genes with multiple alleles unless the “test” measures all the alleles.


Testing Criteria appendix 1

Conditions in panel test (please expand table if required)

OMIM standard name of condition and symbol OMIM number


Testing Criteria appendix 2

Genes in panel test (please expand table if required)HGNC standard name and symbol of the gene HGNC

numberOMIM number


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