In recent months, we have received several inquiries about data processing issues. As a result, we have now compiled a list of frequently asked questions (FAQs) as an aid for new users:

1. What does BOADICEA do?
2. Who can use BOADICEA?
3. What information does BOADICEA use to determine risks?
4. What information is not taken into account?
5. How can I avoid underestimating risks?
6. Why are age at last follow up and year of birth vital to risk estimates?
7. Should I estimate age at last follow up and year of birth if they are missing?
8. Are risk estimates sensitive to variations in the age at last follow up?
9. If an age at last follow up is uncertain, can I run several calculations to see the effect of different ages?
10. Some BWA results do not match results from earlier versions of BOADICEA. Why?
11. How do you define breast cancer?
12. How do you define ovarian cancer?
13. How are BRCA1 and BRCA2 mutations defined?
14. Should information on prophylactic surgery be used?
15. Can I use BOADICEA to estimate risks for populations outside the UK?
16. Are there any family history data that could cause problems?
17. Can BOADICEA estimate risks for Ashkenazi Jewish individuals?
18. Has the BOADICEA model been validated?
19. Why has the program calculated mutation carrier probabilities but not cancer risks?
20. Why has my pedigree drawing window failed to appear?
21. Why has my pedigree drawing failed?
22. If my pedigree drawing fails, will this affect the calculated mutation carrier probabilities and cancer risks?
23. Why are all family members shaded in pedigree drawings with no affected individuals?
24. Why are some family members missing from the selection list on the SWITCH TARGET Web page?
25. Can I download the computed results in a text file?
26. Can I use symbols to distinguish different types of cancer in pedigree drawings?
27. Are twins marked on pedigree drawings?
28. Why has an 'unknown' age at cancer diagnosis been modified on input?
29. Can I upload Cyrillic pedigree files for processing?
30. Why are column headers misaligned in my BOADICEA import/export format file after I modified it in Excel?
31. Can I enter pedigree data sets retrospectively?
32. Do you plan further refinements to the BOADICEA model?
33. Have you considered UK Data Protection Principles?
34. Are my data secure on the Web server?
35. What is your policy on bugs and software defects?
36. Which paper should I cite when describing results generated using the BOADICEA Web Application?
37. What is the difference between a mutation search and direct gene test? Why does BOADICEA distinguish between these different genetic test types?
38. How sensitive are current mutation search methods in the UK?
39. What is the difference between 'lifetime risk' and 'remaining lifetime risk'? What are the breast/ovarian cancer risks shown in the BOADICEA results tables?
40. My pedigree includes both Ashkenazi Jewish and non-Ashkenazi Jewish family members. How will BOADICEA compute risks in this case?

BOADICEA calculates the risks of breast and ovarian cancer in women based on their family history. It also calculates the probability that they are carriers of any cancer-associated mutations in the BRCA1 or BRCA2 gene.

• The family history of breast, ovarian, prostate and pancreatic cancer
• Information on any BRCA1 or BRCA2 testing that has been performed
• The ages at which these cancers were diagnosed in the family
• Age information on unaffected family members
• Ashkenazi Jewish origin
• Information on cohorts

BOADICEA does not take into account information on:

• Family history not listed above
• Risk factors other than genetic status or family history

Ideally, the input pedigree should be complete, up-to-date and free of errors. However, we recognise that in practice, it is often very difficult to collect family history data, and that no pedigree is ever truly complete.

Errors and omissions in the input pedigree data can lead to a misspecification of risk, and so the user should consider these data carefully. The following actions will help to prevent this from happening:

(i) All individuals with cancer must be recorded with an age at diagnosis, an age at last follow up and a year of birth. If any of these parameters are missing, they should be estimated.

(ii) The year of birth and age at last follow up should be supplied for all family members, or as many as possible.

(iii) If a family member has had a prophylactic mastectomy or oophorectomy, it is advisable to set her age at last follow up as her age at the time of the operation assuming she has subsequently remained free of cancer. These procedures are known to reduce the risk of developing breast cancer.

(iv) Genetic test results must be included.

(v) Family members of Ashkenazi Jewish origin must be recorded.

When calculating risks, BOADICEA only uses family members with a valid year of birth and age at last follow up. If either of these parameters is set to zero or 'unknown', the individual will be ignored in the risk calculation. As a result, these parameters are vital to BOADICEA risk estimates.

Yes, certainly in cases where the person is known to have developed cancer. For example, consider a pedigree where the consultand is 30 years of age in 2007, and the consultand's grandmother died of ovarian cancer at age 40, but there are no details of the grandmother's year of birth. In this case, we should make some estimate of the grandmother's year of birth (e.g. 2007 - 30 - 25 - 25 = 1927) and include this information in the input pedigree. Otherwise, mutation carrier probabilities and cancer risks will be underestimated.

Yes, in general, increasing the age at last follow up of a given family member will drive mutation carrier probabilities and cancer risks down, and vice versa. Hence, age at last follow up should always be specified.

Yes, we would encourage users to do so. There are no restrictions on program use. If an age at last follow up (or diagnosis) is uncertain, you can run the program several times with different ages to see how this affects the calculated results. This will demonstrate how sensitive the model is to the uncertainties in your input pedigree data set. You can download your pedigree data at the end of your initial processing run. Once you have saved the file, it can be easily modified and uploaded again for reprocessing to test the sensitivity of the model in this way.

The BWA uses that latest version of the BOADICEA computer model to calculate risks. This new model incorporates information on prostate, pancreatic and male breast cancer, and incorporates details of all cancer diagnoses (not just the first). These parameters were not considered in the earlier models, and therefore some results will differ from those calculated previously. The BOADICEA model has evolved necessarily during recent years, and will continue to do so.

Breast cancer is taken to mean invasive breast cancer. You may also include ductal or lobular carcinoma-in-situ. However, the program was not developed for in-situ cancers, so the accuracy on the program is less clear in this case.

For the purposes of BOADICEA, ovarian cancer means invasive epithelial ovarian cancer. Non-epithelial tumours (i.e. germ cell tumours) of the ovary are not associated with BRCA1 or BRCA2 mutations and should not be included. Borderline (low-malignancy potential) ovarian tumours are also not thought to occur at increased frequency in BRCA1 or BRCA2 carriers and should probably be excluded. However, the data are uncertain on this point.

Ovarian cancer is usually taken to include cancers of the fallopian tube, which also occur at increased frequency in BRCA1 and BRCA2 carriers. It may also include primary malignancies of the peritoneum. Cancers of the uterus (body or cervix) should not be included.

By "mutation positive" BOADICEA means a mutation that is thought to be associated with an increased risk of cancer.

There are several types of mutation in BRCA1 and BRCA2. Some are thought to be associated with cancer risk (deleterious mutations). Others are thought to be unrelated to cancer (polymorphisms). For many mutations, it is uncertain whether there is an association with cancer or (variants of uncertain significance, or VUS). You are advised not to include VUSs as mutations.

As a general rule, deleterious mutations include:

• Frameshift mutations
• Nonsense mutations
• Splice site mutations involving the consensus splice sequence (+1/+2/-1/-2 positions)
• Large deletions or duplications (involving whole exons) or other large rearrangements
• A limited number of missense mutations (amino-acid substitutions), principally involving cysteines in the ring finger of BRCA1

Polymorphisms include all variants which occur at significant frequency in the population (1% or more).

Variants of uncertain significance include:

• In-frame deletions or insertions
• Splice-site mutations not involving the consensus splice sequence
• Most missense mutations

The Breast Cancer Information Core (BIC) contains information on many thousands of reported mutations and whether or not they are likely to be deleterious.

If a family member has had a prophylactic mastectomy or oophorectomy, it is advisable to specify her age at last follow up as her age at the time of the operation, especially if other cancers have been diagnosed subsequently.

If the target (the index or subject of the risk calculation) has had an oophorectomy, then BOADICEA should not be used to compute risks for that individual because information on prophylactic surgery is not taken into account explicitly. However, BOADICEA can still be used to calculate risks for other family members under these circumstances.

The current version of BOADICEA has been developed primarily using data for the UK, and is therefore most applicable to the British population. It should, however, work reasonably well in other Western populations.

Certain other populations have higher frequencies of BRCA1 and/or BRCA2 mutations. These include Iceland, Poland and the Netherlands. Modifications to the risk calculations may be required for these populations.

The program has not been evaluated in populations at lower risk of breast cancer (such as far Eastern or developing countries). Predictions in these populations (particularly of the cancer risk) are likely to be unreliable.

BOADICEA has been developed and evaluated using data from families with a variety of family histories or breast and ovarian cancer. Some situations in which the current version of the program may not work well include:

• A strong family history of prostate or pancreatic cancer
• A family history of early onset breast cancer and sarcoma that may suggest Li-Fraumeni syndrome
• Predicting ovarian cancer risk where the target (index or subject of the risk calculation) has tested negative for BRCA1 and BRCA2 mutations. BOADICEA assumes that the genetic susceptibility to ovarian cancer is due to mutations in BRCA1 and BRCA2 only (a polygenic component is not assumed in this case). This is a limitation in the current model. As a result, ovarian cancer risks computed for individuals who have tested negative for BRCA1 and BRCA2 must be treated with caution.
• Care should also be exercised in families with a strong history of ovarian cancer. The risk of ovarian cancer may be underestimated in this context.

There is a specific allowance for families of Ashkenazi Jewish ancestry. This option should be used for individuals known to be of Ashkenazi Jewish descent.

This Web site provides access to BOADICEA Web Application version 1.0 (BWA 1.0). A validation study describing the performance of this latest version of BOADICEA and other risk models has been published recently in the Journal of Medical Genetics:

Antoniou A., Hardy R., Walker L., Evans D.G., Shenton A., Eeles R., Shanley S., Pichert G., Izatt L., Rose S., Douglas F., Eccles D., Morrison P., Scott J., Zimmern R., Easton D. and Pharoah P., Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics, Journal of Medical Genetics, advance online publication 15 April 2008 (doi:10.1136/jmg.2007.056556).

To access this paper via PubMed click here

Previous versions of the BOADICEA model have been assessed in the following papers:

Barcenas C.H., Hosain G.M.M., Arun B., Zong J.H., Zhou X.J., Chen J.F., Cortada J.M., Mills G.B., Tomlinson G.E., Miller A.R., Strong L.C. and Amos C.I. 2006. Assessing BRCA carrier probabilities in extended families, Journal of Clinical Oncology, 24(3), 354-360.

Antoniou A.C., Durocher F., Smith P., Simard J., INHERIT BRCAs program members and Easton D. 2006. BRCA1 and BRCA2 mutation predictions using the BOADICEA and BRCAPRO models and penetrance estimation in high-risk French-Canadian families, Breast Cancer Research, 8(R3), doi:10.1186/bcr1365.

In order for BOADICEA to calculate breast and ovarian cancer risks, the target (the index or subject of the calculation) must be either: (1) a female who is unaffected by cancer, or (2) a female who has developed one breast cancer only. As a result, cancer risks will not be computed if the target has developed other cancers, or the target is male.

Similarly, BOADICEA calculates breast and ovarian cancer risks for individuals with a maximum age of 80. Therefore, cancer risks will not be calculated if the age of the target of 80 years or greater.

When you request a pedigree drawing, the program attempts to display the drawing in a popup window. Some browsers and firewalls block popup windows. In particular, recent versions of Microsoft Internet Explorer or Firefox generate a message similar to 'The current Web page has attempted to open a popup window. Allow popup windows from this site?' If you OK this, then the pedigree drawing window should appear from then on. If the pedigree drawing window still fails to appear, you may need to make further adjustments to your browser or firewall settings.

The program also generates a pedigree drawing for the processing report PDF. However, this runs as a separate process. Therefore, if your popup window fails to appear, it is still likely that your pedigree drawing will appear as normal in the PDF.

The R/Kinship pedigree drawing program sometimes fails to draw the input pedigree and returns an error code. When this happens, the popup window displays the message 'The Kinship drawing package failed to draw your pedigree'. Our initial tests show that Kinship will draw most pedigrees successfully. However, the graphical representation of large and complex pedigrees is a complex issue, and all pedigree drawing packages have limitations. We aim to establish more clearly why these failures occur in the future.

No, the pedigree drawings and computed risks are generated by separate software modules. Therefore, if your pedigree drawing fails, this will not affect the computed risks.

This is a bug in the pedigree drawing module. We intend to rectify this problem in the next version of the BWA.

In order to calculate risks, the target (index or subject of the risk calculation) must have a valid year of birth and age at last follow up. As a result, the SWITCH TARGET Web page returns only family members who have both a valid year of birth and age at last follow up.

No, at present the computed risks are only displayed onscreen and in the processing report PDF. Whilst users can easily cut and paste these numbers into a separate file, we recognise that this is inconvenient. As a result, we intend to add a link to a results text file in the next version of the program.

No, although the Kinship package does support the use of different symbols, we have not yet implemented this in the program. We intend to do this in the next version of the program.

No, although twins are listed in the pedigree tables, they are not explicitly identified in accompanying pedigree drawings. We intend to do this in the next version of the program.

When users input pedigree data, the program checks all cancer diagnosis ages. If an age at diagnosis is set to 'unknown', but at the same time, the person has a valid age at last follow up, then the age at cancer diagnosis is reset to the age at last follow up. This is to prevent an underestimation of risk.

No, this is not possible at present. We investigated this but found that users represented phenotypic data in different ways in Cyrillic files. As a result, it has not been possible to write a module to upload Cyrillic files yet. Nonetheless, we will continue to explore ways of achieving this in the future.

BOADICEA import/export data files include text headers at the top of each data column to identify it. If you save a pedigree in an import/export data file, you can open and modify it in Excel. However, when the file is saved again after modification, the column headers can become misaligned, as Excel inserts just one whitespace character between each data column. If necessary, this can be easily corrected by editing the file further. The column headers are included solely to make the data files more readable for the user, and are ignored by the BOADICEA program when the file is uploaded.

Under some circumstances, users may wish to build pedigrees online that have not been updated for a year or more. Unfortunately, the current online data entry scheme may not be well suited to this, as it was designed specifically to capture pedigrees that are up to date (the Web pages were based on family history forms used in clinics). At present, the simplest way to process a pedigree that is not up to date is to use the BOADICEA data upload facility.

Yes, we plan to improve the program to incorporate the following additional features:

• Extension of online pedigree building to families of arbitrary structure
• Subtypes of breast and ovarian cancer
• Variation in risk by type of mutation
• Other genes (TP53, ATM, CHEK2, PALB2, BRIP1, FGFR2, TNRC9, MAP3K1 etc)
• Modifications for other populations
• Other risk factors, including parity, early menopause and mammographic density

Yes, we have designed the program with UK Data Protection Principles in mind. In particular, we have kept data capture to a minimum, and tried to avoid using patient identifiable information wherever possible. This ensures that all data submitted to the server are strongly anonymised, as recommended in the Caldicott Committee Report on the Review of Patient-Identifiable Information. We always encourage users to supply anonymous codes instead of forenames wherever possible.

Similarly, we always encourage users to logout at the end of their session, so that their data are deleted immediately from the Web server. Any data sets left on the server are always deleted when the session times out. This ensures that only very small quantities of data are stored on the server at any one time.

All computers connected to the Internet are at risk of malicious attack, and we cannot guarantee that the Web server will remain uncompromised in the future. However, we have taken reasonable steps to minimise the effect of a malicious attack should one occur, and to ensure that pedigree data are secure whilst being processed. All data transmissions to and from the server are encrypted, and only very small quantities of data are stored briefly in a private directory.

We always encourage users to supply anonymous codes instead of forenames wherever possible. Nevertheless, pedigree data submited to the server will always be strongly anonymised.

It is also important to note that the personal details supplied by users during registration are never merged with pedigree data, so that user anonymity is maintained.

All substantial computer programs contain bugs and defects. Software testing can help to detect defects, but the programming community has yet to find a way to eliminate them completely. The BWA is a substantial computer program that uses several third party software packages. Each version of the program that is made available for general use will be thoroughly tested. However, there is always a possibility that some software defects may remain undetected. The detection and elimination of software defects is of the upmost importance. Therefore, we always urge users to contact us if they suspect that any results generated by the program are in error. Under these circumstances, we will always verify results to ensure that the program is functioning correctly. Similarly, we always try to disseminate feedback from beta testers so that all users are made aware of these issues.

The latest BOADICEA model is described in a paper published recently in the British Journal of Cancer. This Web site provides access to BOADICEA Web Application version 1.0 (BWA 1.0). Users should cite this new paper when describing results generated with BWA 1.0:

Antoniou A.C., Cunningham A.P., Peto J., Evans D.G., Lalloo F., Narod S.A., Risch H.A., Eyfjord J.E., Hopper J.L., Southey M.C., Olsson H., Johannsson O., Borg A., Passini B., Radice P., Manoukian S., Eccles D.M., Tang N., Olah E., Anton-Culver H., Warner E., Lubinski J., Gronwald J., Gorski B., Tryggvadottir L., Syrjakoski K., Kallioniemi O-P., Eerola H., Nevanlinna H., Pharoah P.D.P. and Easton D.F., The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions, British Journal of Cancer, advance online publication 18 March 2008 (doi: 10.1038/sj.bjc.6604305).

To access this paper via PubMed click here

A mutation search involves reading large parts of the gene, whereas a predictive or direct gene test is an analysis for a known mutation in a family. BOADICEA distinguishes between these two types of genetic test on the basis of their sensitivity. In particular, the current BOADICEA model (implemented in BWA version 1.0) assumes that mutation searches only detect 70% of BRCA1 mutations and 80% of BRCA2 mutations, whereas direct gene tests are assumed to be 100% sensitive. As a result, the model allows for the possibility that a mutation has been missed by a mutation search. The BRCA1/BRCA2 mutation search sensitivities implemented in BWA version 1.0 were based on UK data available when the BOADICEA model was originally developed. However, the next version of the software (BWA version 2.0, see here for more details) will include a new Model Parameters module that will enable users to set their own mutation search sensitivities prior to running a risk calculation.

Mutation search sensitivities will always vary according to the screening methods used. However, mutation searches employed in UK clinical genetics centres commonly achieve sensitivities of 90-95% for both BRCA1 and BRCA2 (as of September 2009).

Lifetime risk is the risk of cancer occurring between ages 1-80 e.g. lifetime risk of breast cancer in the UK population is around 9% by age 80 (the risk for a newborn female in the general population). You can obtain a realistic estimate of lifetime risk in BOADICEA by setting the age of the consultand (index, or subject of the risk calculation) to 20 years old, and using the risk computed at 80 years of age.

Remaining lifetime risk is the risk of cancer occurring between the individual's current age and 80 (say for an individual in their 30s or 40s), conditional on the disease experience of the individual up to that point (whether she has remained unaffected or developed unilateral breast cancer).

When you run a BOADICEA risk calculation, the program will initially search the input pedigree for family members with Ashkenazi Jewish (AJ) ancestry. If the program finds one or more AJ family members, then it will reset the BRCA1/BRCA2 mutation frequencies to AJ values before the risk calculation is processed.

The BOADICEA program must process each pedigree with a single set of BRCA1/BRCA2 mutation frequencies. In practice, this means that the program must assume that either: 1. all family members have AJ ancestry, or 2. all family members have non-AJ ancestry. Hence, if your pedigree includes both AJ and non-AJ family members, the program will assume (for modelling purposes) that all family members have AJ ancestry and it will compute risks on that basis.

Under some circumstances, the input pedigree may include one or more AJ family members, but the individual being counselled (target, index or subject of the risk calculation) is not a genetic descendant of any of these people. For example, if the target has a maternal uncle who marries someone of AJ origin, then the index is not a genetic descendant the uncle's AJ partner. Under these circumstances, it is advisable to specify that all family members have non-AJ ancestry.

If you have any questions concerning the BOADICEA Web application, please contact Dr Alex Cunningham (E-mail alex@srl.cam.ac.uk)