DNA probe technology: implications for service planning in Britain J. Rona, A. V. Swan, R. Beech, M. Wilson, F. B. Kavanagh, Brown, C. Axtell and Mandalia

Rona RJ, Swan AV, Beech R, Wilson OM, Kavanagh FB, Brown C, Axtell C, Mandalia S. DNA probe technology: implications for service planning in Britain. Clin Genet 1992: 42: 186-195.

R. 0. C. S.

For certain genetic conditions DNA testing identifies carriers and determines the risk status of foetuses, thus helping parents to make more informed prenatal decisions. Data, collected from three genetic centres in England and Wales from August 1986 to July 1990, are used to describe trends in demand for DNA testing, the impact of DNA tests on carrier risk assessment, and the use of DNA tests in relation to pregnancy outcome. Altogether the data include 23 388 subjects and 681 pregnancies in 8738 families divided into five cohorts by year of entry and referral. The most frequent gene disorders referred to the genetic centres are currently being tested or will soon be tested. For these disorders the initial high level of activity has declined and may have reached steady state. Demand for DNA services is high for cystic fibrosis and Duchenne muscular dystrophy, intermediate for Huntington’s disease, and low for adult polycystic kidney disease, phenylketonuria and tuberous sclerosis. Based on these findings we suggest that demand for DNA tests will be high in serious, untreatable and slow progressing conditions with early onset; intermediate for conditions affecting intellect and neurological integrity with later onset; and low for treatable, late-onset conditions, or those for which there is evidence of heterogeneity. and variable penetrance. It would be helpful to assess the extent to which this view of demand is confirmed when the new disorders being DNA tested are considered and for the pattern of activity of DNA testing for some types of cancer. Since no DNA centre could offer a fully comprehensive testing service, it is recommended that a structure is created to audit overall activity, assist in policy formulation, and influence supraregional service organisation, in order that the spread of DNA services be planned as effectively as possible. This structure would facilitate monitoring of the evolution of contract specifications agreed by commissioners and providers on a regional basis.

Department of Public Health Medicine, United Medical and Dental Schools, of Guy‘s and St. Thomas’s Hospitals, London, UK

The Department of Health (DOH) commissioned our research unit to evaluate the impact of recombinant DNA technology on the services provided in genetic centres. The study was carried out in three centres (St Mary’s Hospital and the Royal Children’s Hospital, Manchester, University Hospital of Wales, Cardiff, and the Institute of Child Health in London). These centres participated in a Special Medical Development (SMD), funded by the DOH, from August 1986 to July 1990. Our study monitored the transition of DNA services from a research to a service-based application. The overall aims of the evaluation were to assess the community benefit and genetic service cost of DNA analysis, and to provide a framework for estimating the resources required for developing these services. Papers on baseline demand and the 186

Key words: demand - DNA testing

- service planning

- monitoring

Dr R. J. Rona, Department of Public Health Medicine, St Thomas’s Hospital. Lambeth Palace Rd, London SE17EH. United Kingdom Received 23 December 1991, revised version received 3 April, accepted tor publication 6 June 1992

costs of DNA probe services have been published (Rona et al. 1989, Beech et al. 1989). This paper discusses trends in the demand for genetic services and DNA testing, changes in carrier risk estimates related to DNA testing, and changes in foetal risk estimates for at-risk pregnancies and the subsequent outcome of these pregnancies. The demand for highly specialised DNA testing can be influenced by factors such as the incidence of the disorder, patients’ felt need, the referring professional’s perception of patient benefit, the specialist’s perceived need, and the capability of the laboratory to supply the service. The contribution of each of these elements may vary by disorder and change over time. Together these reflect the number of genetic referrals and the percentage for which DNA probe tests are requested. For

DNA probe testing and service planning convenience the terms demand or use of service will be used throughout the paper. These terms are not meant to contrast demand with need or supply.

been due to reasons unrelated to the demand for services in the genetic centres.

Data structure Subjects and methods

All patients attending the three genetic centres were included in the study, except for the Royal ManChester Children’s Hospital where only cystic fibrosis (CF) referrals were included. As explained elsewhere (Rona et al. 1989), two fieldworkers extracted data from case-notes onto two questionnaires: the first for new entries to the study and the second for any subsequent follow-up of families with a single gene disorder. The forms were divided into two parts: family and individual information. This paper considers individual variables including diagnosis using hlcKusick’s classification (1988), age, availability of DNA testing, and percentage of families DNA tested for selected conditions. A separate form of follow-up of pregnancies at risk for a Mendelian disorder recorded which prenatal tests were used, side effects, modification of foetal risk, and pregnancy outcome. Only pregnancies in referrals to genetic centres in the period August 1986-July 1989 were covered by our study. Pregnancies occurring after that date were not included because their outcome was not known at the end of the data collection period. Initial estimates of at-risk individuals and foetuses were derived from pedigree information. For some diseases other information was included in estimating risk, e.g. age in Huntington’s disease (HD) and serum creatinine kinase activity in Duchenne muscular dystrophy (DMD). Information on risk was mostly obtained from casenotes. In some cases comments in the notes alerted the fieldworkers to the existence of DNA probe results and they made direct enquiries to the DNA laboratory. There are three components to the work load of genetic departments: the number of new families referred to genetic centres, the number of appointments required, and the activity generated by each encounter in terms of use of resources and time. The main focus of this paper is on the number of new families referred to the centres during the evaluation period. We also give a brief account of the average number of visits per family to genetic centres for three genetic disorders. In this evaluation the intensity of each encounter was explored in terms of tests but genetic counselling itself was not part of the evaluation. When exploring trends over time, we contrasted the period 1986-88 to the period 1988-90. We prefer this approach and not trends by year of referral to avoid possible fluctuations in the shorter period of time that may have

Fig. 1 shows the study design by year of entry and year of study. Each cohort included families known to the centres prior to 1986 when our study started and newly referred families. The group previously known included a larger proportion of subjects in cohort A than in subsequent cohorts and were usually more advanced in their assessment than the newly referred families. To eliminate this bias the families referred to the genetic centres before August 1986 were analysed separately. Results

The results are given in three sections: 1. Demand, 2. DNA testing and carrier risk modification, and 3. Fetal risk modification and pregnancy outcome.

Characteristics of demand Families are grouped according to cohort and mode of inheritance (Table I). Comparison of cohorts A, B, C and D indicates that the total number of new families per year entering the study decreased slightly from 198687 to 1987-88, markedly from 1987-88 to 1988-89 and increased moderately in 1989-90. There were differences by mode of inheritance. For X-linked (X-L)disorders the number of families referred has been diminishing continuously. For autosomal recessive (AR) disorders maximal referral numbers were in 1987-88, while for autosomal dominant (AD) and other disorders there was a decrease up to 1988-89 and a slight increase subsequently. Table 2 shows the number of families referred for the most common single gene disorders according to centre. The conditions with highest referral frequency were CF, DMD, HD, myotonic dystrophy (MD), neurofibromatosis 1 (NFl), and adult polycystic kidney disease (APKD). With the

yearof entry

1987-88 1988-89

-

B,

B2

B3

-

-

CI

c2

-

-

-

D,

~

1989-90

187

Rona et al. Table 1. Number of families entered into the study by mode of inheritance and cohort as defined by year of referral to centre. Cohorts Pre-A before 1986'

B 1987-88

C

D

198647

1988-89

1989-90

648 204 398 345

457 376 216 1214

441 453 183 997

278 225 104 685

384 339 86 705

1595

2263

2074

1292

1514

Autosomal dominant (AD) Autosomal recessive (AR) X-linked (XL) Others Total no. of families entered in the study

A

' Families known to the centre before the study started who used the genetic service facilities during the study period.

Becker muscular dystrophy (BMD) and DMD, the largest number of referrals came to the genetic centres before August 1986. The number of new families for these conditions has decreased substantially, especially in the period 1988-90. Fig. 2 illustrates this trend for BMD and DMD by centre. C F new referrals peaked in the period 1986-88 and decreased thereafter in two of the three centres. Table 3 also indicates the percentage of families that had DNA testing. DNA testing was a common feature for MD, CF, Bruton, BMD or DMD, and OTC in all the cohorts, while it was less common

exception of APKD and MD, activity levels for these disorders were high in all three genetic centres. There are several disorders for which we are aware that the referral pattern reflects the research interests of centres, e.g. facio-scapulo-humeral (FSH), M D and limb girdle muscular dystrophy (LGMD) in Cardiff, APKD in Manchester, and XL immunodeficiences and ornithine transcarbamylase deficiency (OTC) in London. For the conditions for which some DNA testing has occurred, Table 3 indicates demand by period of referral. For several disorders, e.g. HD, APKD,

Table 2. Most common single gene disorders by genetic centre over the 4 years of study Manchester N (%I

Autosomal dominant (AD) Acrodysostosis (NO) Charcot-Marie-Tmth (CMT) Huntington's disease (HD) Marfan's syndrome (MS) ficio-scapulo-humeral (RH) Myotonic dystrophy (MD) Nwrofibromatosis' (NFl ) Noonan syndrome (NS) Osteogenesis imperfecta (01) Adult polycystic kdney disease (APKD) Polyposis coli (PC) Retinitis pigmentosa (RP) Retinoblastom (RB) Tuberous sclerosis (TS)

6 (18) 218 (46) 18 (40) 8 (22) 52 (22) 72 (44) 19 (31) 15 (43) 114 (86) 16 (76) 8 (33) 14 (39) 21 (36)

4 (20) 23 (70) 188 (40) 12 (27) 22 (59) 161 (68) 47 (28) 10 (16) 1 1 (13) 15 (11) 4 (19) 1 6 (67) 17 (47) 10 (17)

Autosomal recessive (At?) Limb-girdle muscular dystrophy (LGMD) Cystic fibrosis (CF) Werdnig Hoffman muscular atrophy (WH)

4 (17) 417 (57) 10 (48)

16 (67) 211 (29) 4 (19)

26 (27) 170 (38) 16 (31) 38 (38)

-

SO (52) 148 (33) 1 1 (21) 15 (15) 2 (9)

1 (2)

2 (4)

X-linked (X-L) Becker muscular dystrophy (BMD) Duchenne muscular dystrophy (DMD) Haemophilia A (HA) Fragile X (FX) Ornithine.transcarbamylase deficiency (OK)

Unknown Angelman's syndrome (AS)' Mode of inheritance not Well established

188

Cardiff N (%I

8 (40)

London N (%I

8 (40)

4 (12) 64 (14) 15 (33) 8 (22) 24 (10) 45 (27) 32 (52) 9 (26) 4 (3) 1 (5)

Total N

20 (loo) 33 (1 00) 470 (100) 45 (100) 37 (100) 237 (100) 165 (100) 61 (100)

5 (14) 27 (47)

35 (100) 133 (100) 21 (100) 24 (100) 36 (100) 58 (100)

4 (17) 108 (15) 7 (33)

24 (100) 736 (100) 21 (100)

21 (22) 25 (48) 48 (48) 20 (91)

97 (100) 445 (100) 52 (100) 101 (100) 22 (100)

42 (93)

45 (100)

-

127 (29)

DNA probe testing and service planning Table 3. Genetic disorders for which at least one family has been DNA tested by cohort Before 1986 DNA tested NO.

1986-87

-

DNA tested NO. NO. (%)

NO. (%)

1987-88 DNA tested NO. NO. (%)

1988-89 NO.

DNA tested No. (%)

Total

1989-90

No.

DNA tested No. (X)

No.

DNA tested No. (%)

469 237 165 133 734 45 24 16 17 13 52 101 97 443 22 10 15

40 (9) 95 (40) 2 (12) 5 (4) 406 (55) 5 (11) 3 (13) 1 (6) 8 (47) 3 (23) 18 (35) 2 (40) 35 (36) 190 (43) 12 (55) 1 (10) 1 (7)

-

HD MD NF APKD CF

220 90 47 72 80 9 9 5 2 1 10 17 44 263 10 1

As LGMD PKU Bruton ECTD HA Fx BMD DMD

On: NS LS

88 52 30 19 152 10 2 6

9 2 22 21 19 81 4 6 2

1

5 (6) 16 (31

75 (49) -

4 (44)

10 (45) 6 (32) 24 (30) 1 (25) 1 (17)

-

94 40 24 26 241 7 7 2 2 5 9 37 18 49 5 2 4

33 27 29 3 74 9 4 3 3 2 5 15

7

5 (15) 7 (26)

-

-

30 (41)

-

1 (25) 1 (25) 1(W

1 (20) -

29 1

2 (29) 7 (24) 1 (100)

8

1 (13)

-

-

34 28 35 13 187 10 1

-

1 3 6 11 9 21 2 1

-

1 (3) 4 (14) 2 (6) 1 (8) 161 (86) 5 (50)

-

l(11) 5 (56) 9 (43)

-

-

PKU=Phenyfketonuria: Bruton- Agammaglobulinemia (AG Bruton); ECTD- Anhidrotic ectodemai dysplasia: NS-Norrie’s syndrome; LS-Lowe’s syndrome. For other abbreviations. see Table 2.

for HD, APKD and PKU. For some disorders there may be fewer families DNA tested in the latest cohort but this is probably due to their shorter contact with the genetic centre. A blood specimen has been stored for most of the families with the conditions in Table 3. There are approximately another 20 disorders less frequently referred

80 70

60

-

’

40-

30

-

20

-

10

-

0-L

vre-ee

1881-88

1988-90

year

=

Mancheater Cardlt? London Fig. 2. New referrals of families at risk of D M D and BMD.

to genetic centres for which DNA testing is also available, e.g. adrenal hyperplasia (defect of 21 hydroxylase) and Aldrich syndrome. Fig. 3 shows the average number of visits per family for HD, DMD or BMD, and C F in the initial year of referral, and in the first and second follow-up years. The denominators are based on the number of families for whom a follow-up visit was possible to the centre, calculated on an annual basis. Thus families referred in 1989-90 were excluded from first and second follow-up denominators and families referred in 1988-89 were excluded from the second follow-up denominator. The below unity average centre visits per family in the initial year for H D and DMD or BMD indicates that some families were not seen in the genetic centre or, possibly, were visited at home. Approximately half the families with HD and DMD or BMD who visited the centre in the first year, visited the centre in the first follow-up year, decreasing to approximateIy 25% in the second follow-up. For C F proportionaIly fewer families visited the centre in the first follow-up, but there was an increase in the second follow-up that may reflect the carrier DNA testing of subjects in families with a history of CF. Between August 1986 and July 1990, 10698 males and 12 690 females entered the study. AR or “other” referrals were usually younger. For AD conditions there were relatively few individuals under 15 in cohort pre-A and to a certain extent in cohort A, but this was not so in cohorts B, C and D. For X-L disorders there were more males under 15 years than females while a large percen189

Rona et al. 1.2

-

analysis and this explains the large percentage of individuals with a near 100Y0probability of being a carrier. With the exception of HD, in which predictive carrier risk is rarely undertaken, DNA probe testing identifies most high- and low-risk carriers. This increase in precision was particularly noticeable for MD, APKD, CF, BMD, DMD, and OTC. For other conditions such as agammaglobulinaemia (Swiss type) and dyskeratosis congenita, DNA testing was also informative but the tested population was small.

10.8 -

M

e a 0.8

-

0.4

-

n

DNA testing and foetal risk assessment

0.2 -

0Initial year

First F-U

Second F-U

Period of visit

a

HD DMD and BMD CF Fig. 3. Average centre visits per family HD. DMD and BMD.

and CF.

tage of females were 16 to 30. This is compatible with X-L disorders with affected males and at-risk females concerned with carrier status during their reproductive years. Individuals were usually referred to genetic centres by three specialties: paediatrics, general practice, and obstetrics and gynaecology. Genetics centres initiated a large number of referrals by frequently inviting the extended family to attend the centre. Family members invited by the genetic centres formed the largest group of referrals in cohort pre-A (57.50/0),but this percentage diminished subsequently (between 28% and 10Y0). Omitting centre-generated referrals, patients sent by paediatricians increased from 27% for cohort A to 37% for cohort C . General practitioners’ referrals (around 16%) and referrals from obstetricians (around 17%) have been stable. Referrals from other British genetic centres have steadily declined, reflecting increased self-reliance. Given the relatively small number of neurologists, this specialty referred a sizeable (7%) number of referrals to the genetic centres reflecting the large number of mapped neurological disease genes. The impact of DNA probes on carrier risk precision

In Table 4 changes in carrier risk before and after DNA testing are given for disorders tested for most of the evaluation period. Obligate carriers, based on pedigree information only, were included in this 190

Between August 1986 and July 1989,681 pregnancies at risk of a single gene disorder were entered in the analysis. Six disorders made the major contribution to the total pregnancies at risk including 179 pregnancies at risk of CF, 148 at risk of DMD or BMD, 44 at risk of HD, 30 at risk of MD, 25 at risk of HA and 21 at risk of APKD. In Table 5 , the risk of a foetus being affected according to the genetic disorder is shown for the sub-group of pregnancies where DNA probe tests were used on both the foetus and the parents. Of the overall number of pregnancies covered by our study, this sub-group accounts for 74% of the C F pregnancies, 33% of the DMD and BMD pregnancies, 39% of the H D pregnancies, 40‘1/0of the MD pregnancies, 28% of the HA pregnancies and only 14% of the APKD pregnancies. There were too few APKD pregnancies DNA tested for meaningful assessment. For CF, results were informative in 126 out of 133 pregnancies tested in parents and foetus and for DMD or BMD in 41 out of 49 pregnancies. Table 5 does not include pregnancies in which only the parents or foetus were DNA tested. For DMD parental DNA testing markedly reduced the estimated risk of an affected foetus in a large number of couples. For two conditions, C F and BMD or DMD, the number of pregnancies was sufficiently large to assess changes in discriminatory power over time by comparing pregnancies started in the period 1985-87 and the period 1988-89. There was a clear trend that for both conditions the discriminatory power increased over time (Table 6). Using Fisher’s exact test we assessed whether the decrease of uncertain cases (between 6 and 85%) in the two periods was significant. For C F the decrease was not significant (1 tail p=0.19). However, for DMD or BMD the decrease was equal to the conventional cut-off point (1 tail p =0.05). Data on outcome are available for 85Y0 of the pregnancies covered by our study. For HD all the foetuses found to be at negligible risk for the disease continued the pregnancy, while parents whose

DNA probe testing and service planning Table 4. Distribution by carrier risk status for common DNA tested disorders before and after DNA probe testing (only women included for X-linked disorders)

04% Autosomal disorder HD Before (%) After (%)

MD APKD

CF

Before (%) After (%)

36.4 48.8 25.7 34.6

Before (%) After (%)

25.6 38.5

Before (%) After (%)

X-linked disorder Bruton Before (%) After (%) HA

Before (%) After (%)

BMD

Before (%) After (%)

DMD

OX

Before (%) After (%) Before (%) After (%)

6-15%

16-25%

26-75%

-

1.6 0.8 3.4 1.8

34.1 16.3 22.5 9.7 35.9

1.6

1.2

-

-

6.4 10.5

5.1 0.1 1.3

2.6 1 .o 0.7

-

11.5

11.5 3.8 8.9 5.4 13.3 3.8 16.2 5.3 11.6

23.1 5.4 21.4 5.7 36.2 9.8 36.8 37.2 46.5

-

5.4 5.4 3.8 2.9 12.2 8.2 7.0 9.0

-

7645%

86-95%

1.5

0.5

-

-

7.7

15.3 2.5

0.6

50.0 23.1 41.1 14.3

40.0 9.5 46.5 12.2 27.9 7.0

-

-

3.8

11.5

3.6 10.7 1 .o

-

3.8

0.9

-

-

1.9

4.8

-

-

-

2.3

*loo%

Total

27.9 31.O 48.4 52.2

129 (100%) 129 (100%) 506 (100%) 506 (100%)

38.5 43.5 77.2 84.4

39 (100%) 39 (100%) 1230 (100%) 1230 (100%)

27.0 34.7 35.6 42.8 36.2 42.9 15.3 30.8

26 (100%) 26 (100%) 56 (1 00%) 56 (100%) 105 (100%) 105 (100%) 622 (100%) 622 (1 00%)

18.6 34.9

43 (100%) 43 (100%)

For abbrevations. see Table 2.

foetuses had an estimated risk above l6Y0 chose to terminate. In only one out of 74 ]pregnanciesin CF families was the decision taken to terminate the pregnancy despite a low risk, and parents of only three out of 34 pregnancies decided to pursue a pregnancy despite a high risk. In DMD and BMD no terminations were carried out within the lowrisk group; 12 out of 14 pregnancies were terminated in the group with a risk of 36% or more. A similar pattern was observed for other disorders. Thus the use of DNA tests to clarify risk seems to have been an influential factor on parents’ de-

cisions to terminate or continue a pregnancy to delivery. In the group whose foetuses were at high risk of being affected but who were not tested the percentage of pregnancies not terminated was relatively high regardless of the condition. Information was obtained on whether newborn babies were affected or not in relation to the risk status following DNA testing. None of the newborn babies with a risk 0 to 5% of DMD, BMD and HA was affected. For newborn babies in CF families predicted to have a risk below 5%’ one was diagnosed with the disease.

Table 5. Risk estimate of the foetus being affected by DNA testing in parents and foetus ~~

DNA probes

Risk

HD

MD

APKD

CF BMDor DMD HA

04%

6-15%

1645%

Initial

-

Final

41%

6% 6%

lnitlal Final

94% 6% 17%

42%

Initial Final

-

Initial Final Initial Final lniti Finalk

-

2 % . 67% 1 4% 63% 1 4% 43%

-

59% 10% 29% 1 4%

-

98% 5% 1 8% 6% 57%

1 4%

3645%

86100%

-

-

47% 83% 17% 100% 67%

42%

-

33%

-

-

1%

27%

8% 2%

18%

-

29%

-

-

Total no.

17 (100%) 17 (100%) 12 (100%) 12 (100%) 3 (100%) 3 (100%) 133 (100%) 133 (100%) 49 (loo%) 49 (100%) 7 (100%) 7 (100%)

For abbreviations, see Table 2.

191

Rona et al. Table 6. Distribution of risk of a foetus being affected before and after DNA testing by period of aSSeSment (only those in which parents and foetus were tested included). ~~

Period 1986-87 Risk of being affected

04%

615%

3%

CF Parents and foetus Initial Final

69%

-

BMD or DMD Parents and foetus Initial Final

10% 52%

76% 14%

Period 1988-89 Risk of being affected Total

1 6 4 5 % 3 8 4 5 % 86400%

97% 7 %

-

-

-

24%

10% 10%

5% 5%

19%

-

MI% 6 1 5 % 1645% 3 8 4 5 % 86100%

70 (100%) 70 (100%)

2% 67%

21 (100%) 21 (100%)

10% 75%

-

98%

45%

30%

-

2%

5%

15%

-

31%

20%

Total

51 (100%) 51 (100%)

20(100%) 20 (100%)

For abbreviations, see Table 2.

Discussion Predicted demand

This paper presents an overview of the demand for genetic services in 1986-1990 in three large genetic centres with a strong academic reputation. The results are given according to cohorts arranged by the year the first member of a family was referred to the genetic centre. The strength of this design is that trends over a 4-year period can be shown and the changes in demand by DNA testable condition can be highlighted. A moderate decrease was detected in new families referred in the last 2 years of evaluation (1988-90). In our opinion difficulties of data collection could explain between 15 and 20% of this decrease in the period 1988-89 because only one fieldworker was in post for 5 months of 1988. However, there still remains a consistent decrease in new referrals in the period 1988-90 in comparison to the period 1986-88, of the order of 26% for AD conditions, 32Y0 for AR conditions, 52% for X-L conditions and 37% for “other” conditions. One of the explanations for this trend is that the bulk of families with the most prevalent genetic disorders for which DNA probe testing is available are already in contact with a genetic centre. However, this does not explain the decrease for “other” conditions for which DNA testing is negligible. For HD, MD, APKD, BMD and DMD there has been a continuous decrease in the number of newly referred families in successive cohorts. For CF there was a sharp increase in the number of families, which reached its peak in the period 1987-88. This coincided with a DNA probe becoming available. In the period 1988-90 a moderate decrease in new families w8s detected. The demand pattern for HA is underestimated because departments of haematology now test DNA for this condition. The marked changes observed for disorders with active 192

DNA testing were not seen in other genetic disorders for which either DNA testing is currently less active (e.g. PKU), suitable DNA probes have been introduced only recently (e.g. FX and NFI), or genetic heterogeneity for the disorder has been documented (e.g. TS). We believe that genetic centres may soon reach a plateau of DNA testing for DMD and BMD. With an incidence of 13 per 100000 births (Royal College of Physicians 1989), and with a third of cases being new mutations, the annual demand should be between eight and ten new families per year in a Regional Health Authority (RHA) with typically 3 000 000 inhabitants and 46 000 births a year. Activity will be focused on new referrals and at-risk couples planning to have children known to the centres. Given that the age-specific fertility rate in Britain in 1988 was 63 per 1000 (OPCS 1990), and in the three centres there were 708 females in the age range 18 to 40 years, demand from the families already known to each centre would be between 10 and 20 families per year. This activity would be increased moderately by the testing of 16-year-old girls and through referrals from other RHAs with less established DNA testing services. Furthermore, for a proportion of families, further DNA testing activity may increase work load as a deletion has not been detected or carrier risk remains at an intermediate level. For H D families, the counselling and predictive testing process is very slow (Brandt et al. 1989, Brock et al. 1989, Crauford et al. 1989, Harris et al. 1989). The exception would be predictive testing on an exclusion basis in pregnancy (Meredith et al. 1988). At present it is difficult to predict a steadystate activity for this condition. Dedicated and knowledgeable practitioners will certainly be needed as the counselling issues are very complex. An estimate of demand for this service should take into account new families referred to the centre

DNA probe testing and service planning each year (approximately 10 a :year in established centres), counselling families already known to the centre (20 to 40 sessions in the centre by 100 families), antenatal predictive testing (40 in the three centres in a 2-year period) and incidence (estimated 7 per 100000 births (Royal College of Physicians 1989)). The problem with this estimate is that the large differences in the number of new referrals between the three genetic centres may render an average uninformative. It is inappropriate to base demand estimates on surveys of patients at risk of carrying the deleterious gene. While Meissen & Berchek (1988) found that 65% of their patients intended to take the presymptomatic test, Harris et al. (1 989) reported that there is a fairly large percentage of subjects who initially indicate interest in the test but eventually decide not to take it. For CF, predictions of service demand will be affected by new scientific findings. Since 1987, predictive testing for C F using flanking markers has been available to families with at least one affected child. However, a cystic fibrosis mutation responsible for approximately 70% of the patients has been identified (Rommens et al. 1989, Riordan et al. 1989, Kerem et al. 1989) and already over 70 mutations responsible for the remaining 30Y0 of the patients have been identified. This would imply that the service might develop a two-pronged system - one for those families that come into contact with the health service after an affected child has been born and another provided by population screening (the effectiveness and resource requirements of which should be assessed separately). Nearly 50 newborn babies with C F are currently expected per 100000 births (Royal College of Physicians 1989). Between 1986 and 1989, 179 pregnancies at risk of C F were detected in the three genetic centres (20 prenatal diagnoses per RHA per year). Accepting some under-reporting in our data, an upper ceiling of 30 prenatal diagnoses per RHA per year may be an appropriate estimate of demand. Some extra work load will be generated by DNA testing of families withi a history of CF. In relation to the other common genetic disorders for which DNA probes are available, testing for MD has been very active in terms of presymptomatic testing in adults and prenatal diagnosis, especially when the mother is affected (Meredith et al. 1988). To estimate the demand for MD within a RHA it is necessary to take into account the extent of demand from outside the region. In Cardiff most referrals were from other parts of Britain, while in Manchester and London the majority of the referrals were generated within the RHA. Approximately 85 families were referred within the three RHAs, including prevalent and incident

cases. Allowing for incomplete ascertainment, it is probable that approximately eight to ten families will be referred to a genetic centre per year. Prenatal testing may be concentrated on cases where the mother is affected as this increases the risk of congenital damage to the foetus. For the other frequent genetic disorders, APKD and PKU, we doubt that significant demand for DNA testing will be generated. For APKD the testing has been minimal (Hams et al. 1989). The gene is thought to have complete penetrance with an average age of onset of 40 years (Dalgaard & Norby 1988). The limited interest in prenatal testing may be related to patients’ perceptions of the availability of treatment (haemodialysis and renal transplantation) should the condition become severe. Special interest in DNA testing for a series of rare X-L conditions such as OTC and a few AR disorders such as LGMD has been developed. Although a fairly large number of families with cancers related to genes, e.g. PC and RB, have come to the centres, no major DNA testing was completed. For other disorders, a constant influx of new referrals for NFI, 01, and TS has not entailed DNA testing so far. Probes for FX have become available recently (Yu et al. 1991, Oberle et al. 1991). Families at risk of this condition could make heavy use of DNA laboratory and genetic services as the estimated prevalence of affected individuals is of one in 1250 males and one in 2000 females (Brown 1990). Demand for the use of DNA testing in some types of cancer may increase markedly. For many of these conditions DNA testing will allow resources to be targeted on high-risk patients who need frequent screening. The cost benefit of this activity requires separate assessment. Referral rates to genetic services by other specialities may be related to frequency of problems in these specialities, awareness of practitioners of the services, and the self-reliance of some specialities such as haematology. Whatever the balance between these competing explanations, the effectiveness of the new tools in genetics will be greatly dependent on awareness of the availability of services in clinical genetics. In this respect a minimum education core of clinical genetics should be offered to medical students (Royal College of Physicians 1990), to specialists who use genetic services, and to community health workers who counsel women (Royal College of Physicians 1989). Carrier and foetal risk - precision of estimates

.

The results clearly establish, along with other published works (for example, Brock et al. 1989, Harris et al. 1989, Brandt et al. 1989) that DNA testing

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Rona et al. is a powerful tool for increasing carrier risk precision for a series of genetic disorders. The data based on the first 3 years of the study indicate that DNA testing in pregnancy is a powerful diagnostic test for ascertaining the probability of the foetus being affected by HD, MD, CF, BMD, HA and other less frequent disorders. For the two most frequently tested conditions (DMD and CF), the discriminatory power increased during the period of evaluation. This change was statistically significant only for DMD and BMD. DNA test results in pregnancies may have a marked influence on parents’ prenatal decisions. From the information so far collected we know of only one pregnancy wrongly classified as low risk. In this case the parents continued with the pregnancy and the newborn was diagnosed CF. On the whole, DNA testing is a highly efficacious tool which spares unnecessary terminations and prevents the birth of affected children to parents who wish to avoid the birth of a severely abnormal chiId (Beech et al. in press). Regional organisation in Britain

It is uncertain how DNA services in Regional genetic centres in Britain will expand from the current dynamic situation. DNA services for HA and HB are given by haematologists, and for haemoglobinopathies most samples are tested in a single centre in Oxford and counselled elsewhere. The variable expression for NFI suggests a limited amount of DNA testing and it is premature to estimate how much interest there will be in the use of new DNA probes. There are, for example, a number of conditions that are not infrequent and for which DNA probes for clinical use are available or will be available soon. This group includes spinal muscular atrophy (Melki et al. 1990), Freidrich ataxia, albinism I, CMT and Marfan’s syndrome. It is uncertain to what extent DNA testing for these conditions will overstretch available services. It would be wise to monitor the demand for these conditions in clinical genetics. The genetic centres differ in the way they have developed DNA services. It is becoming less likely that any regional DNA laboratory will provide a comprehensive range of services. A number of specialities will develop DNA laboratories outside genetic services, e.g. haematology and chemical pathology. There are several factors in Britain stimulating fragmentation of services within a region: the low cost of establishing a DNA laboratory; use of DNA probe technology outside the area of camer detection; the simplification of the technology; and the NHS reforms creating an internal market. Two 194

problems need to be addressed: non-geneticists with direct access to a DNA laboratory, and workload distribution between DNA laboratories to ensure that facilities are available for a wide range of conditions with high quality service. Poor performance of small laboratories (Holtzman 1989), should serve as a warning to the indiscriminate proliferation of DNA laboratories. In Britain there are also two organisational features that may prevent the unco-ordinated development of DNA testing laboratories. The consortium of DNA laboratories in Scotland and other areas of Britain that may help to co-ordinate DNA testing services and the professional function undertaken by the Clinical Molecular Genetics Society that has produced a handbook with information on DNA testing in each laboratory up to 1991 and has started to audit the service activity of laboratories on a voluntary basis. The planned organisation of regional DNA laboratory services is important. Unnecessary proliferation of DNA laboratories needs to be avoided. At the same time new applications of DNA technology may necessitate development of new laboratories within regions. The co-ordination of DNA laboratories into a national or supraregional consortium may be a positive step towards coordinated and comprehensive diagnostic services. This should not prevent the formation of structures at national and supraregional level for setting policies, agreeing collaborative supraregional arrangements, identifying areas of over-provision or underprovision, monitoring the impact of services not only at process but outcome level, and setting standards of practice. Acknowledgements We are indebted to Professors P. Harper, R. Harris and M. Pembrey and many of the colleagues in their departments for their help and advice, Ms. B. Fitzsimons.for her helpful comments. Professor W. W. Holland for his encouragement, and Ms. P. Mortley for secretarial assistance. The study was funded by the Department of Health.

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