conditions, f-ronti mild to severe. (iven that most patients have the tests offered to them, the decision about which tests shouldi be widely available becomes paramount. Which conditions arc considered to bc scrious enloLugh to warrant prenatal screeninig and suobsequent ter-mination? '\Xho should decide? As a first step towards a solution the views of scientists, clinicians, managers, and patients as swell as special interest groups, SLuch as those wNith disabilities, need to be determined. TFhe next task is to determine how these potentially conflicting views can be reflected in policy. Once a test is available how, when, and by whom should it be offered to increase the likelihood that the decision to undergo screening reflects more a woman's values and less the social influences inherent in medical consultations? Research on these issues is needed alongside the development of these tests to ensure that we do not become slaves to our own technological wizardry. THERESA M MARTI.AtT Htialth I'sv.t chotog Ut, Rov al ire ilospital SchooloftiMictne, W 20(i Lindon N\;
W5shlart J(G. Prenatal scrcintig for i)tons 2 g
4
5
h
tv n(iromre.
BAItJ7
1991;303:468-9. 24 Attgtist. e inpcratl\c cIaratcer *)ti ictdliacl I! nistri Ij]. j1i tchttlol)gt and the ntcaning ot ;aniticipatcd deitsiotn regret." lnt j chnoltl AssCss l1ltlth (Care 1989;:20)7Marteati T.1. tsYthological Implications ol' prenatal diagnosos. In: i)rile J(), i)ontalt 1), cds. Alnenatal dtagnosis of ftetal (Ibnortlltes. Ltondotn: Springer-Verlag, 1991. Larsson Gi Spatigherg L, Lintdgren 5, lioliliti 13. Screciing lor otl mImatcrrnal iptilotit. A111S HtI ill pregntant wotnci: aI SIldy (are 199(t;2:22;-s. McNeil 13J, l'autikecr SG, Sox [iCi, T vrskv A. (Ott tilt elititation tied of prelerenccs for alterinative tlteraptis. N 1 nogl1 19t12;306: 1259-62. Miarteau iTM. Fratitite} ol itiioriatioit: its ilfltiene u n dcc;s;oi1s of dcttors attd patents. fBr 7So PsYcholI19X9;28: 89-94.
Neonatal screening programme for phenylketonuria SIR,-In Dr Isabel Smith and colleagues' review of screening for phenylketonuria two unrelated points require comment.' Firstly, the authors incorrectly refer to the incidence of phenylketonuria when it was the prevalence at birth (or shortly after) that was determined. If a gene mutation is the cause of the phenvlketonuria onlv alterations in the mutation rate or the expression of the gene will affect the incidence of the condition. On the other hand, the prevalence at birth will also be affected by the duration of the condition, which is influenced by, for example, the rate of spontaneous abortion, and alterations in prevalence mav occur without there being any change in incidence. As it is not known how many affected fetuses are aborted it is not valid to equate incidence with prevalence. Secondly, on the basis that the number of tests exceeded the number of babies born the authors assume that population coverage was almost 100% and that the excess tests were repeat tests. This assumption may, however, be premature as many district health authorities do not link the result of the screening test to the birth notification. rhey therefore do not know either which or how many infants have not been tested. It is a simple expedient to develop administrative gutidelines that will ensure that the test result and birth notification are linked and to produce a weekly listing of those infants who have slipped the net to enable health visitors to chase them up. P 0 D PHAROAH
t)cpartmcnt otiCommu,nity Hcalth, tUniversity ot Liverpool. '() Box 147, Liverpool 1,69 3BX
Simith I1, (took B, Beaslev M. Review oi necoimatal scrcrleing programme for phlcilykctollUria. J3.MJ 1991,303:333-5. 10 Auiguist.
716
SIR.-In their review of the neonatal screening
programme for phenvlketonuria Dr Isabel Smith and colleagues report that the coverage of the programme is thought to approach 100lOO.' This figure is an estimate because of the inclusion of repeat tests but is supported by a recent review of the screening programme in North Hertfordshire Health Authority. This entailed matching results of laboratory tests to the district birth register for a three month cohort of births. Coverage of 98 3'%S was obtained according to the child health records, and this increased to 99-7'% after checks were made with the two screening laboratories concerned. This contrasts with the figure of 93 5'S obtained in an inner city district in the same region. TFhe local programme had no monitoring system to ensttre that a test result was received for every infant, and no one was responsible for coordinating the programme. We plan to improve the quality of the service delivered through the contracting process. KATE JOL.LY
North Hcrtlordshire Hcalth AuthoritV,
Hittlhin. HcIrtordshirc S(G5 IHF
Siiitith 1, (ook 13, B3caslev A. Rc\vicw ot nieoniatal screening programme for phenlivkctonuria. BAI7 1991;303:333-5. If) Aigtlst. 2 HLinter R, Roderick P, RLIta I), Sttiz-Stciger T. "fee)l tn heel"screetitg ot nm.wbtorn it Rterside tealith distritct hv Gtuthrn testetng. Loittdout: London Schotl ott Hvgiene and Tropical AMedicine, 1988.
SIR,-The finding by Drs David Elliman and June Garner that 2% of infants in their health district miss the neonatal screening tests for phenylketonuria and congenital hypothyroidism' indicates how difficult it can be to keep such programmes up to scratch. Their proposals to improve coverage are, however, unlikely in themselves to sustain the desired effect. Making Fhe health visitor responsible for ensuring that every babv in her case load had been tested did not work 30 years ago with the nappy test and is unlikely to do so now, whereas centralisation of both testing and checking procedures after the introduction of blood based screening in 1970 led to a considerable improvement in coverage. Screening samples are usually analysed in regional or subregional laboratories, while checking of negative results against birth lists is done at district level. Even this degree of decentralisation creates problems and in this and other regions we are increasingly experiencing instances where district based systems have broken down in the course of reorganisation or because of staff shortages. The checking itself is often delegated to relatively junior staff and those further up the hierarchy either do not notice that this task is no longer being performed or are unaware of its
of such undertakings there is an argument for maintaining a strong regional involvement in the provision of neonatal screening. RODNEY POLLITT Chairmani, UK Screccning laboratory I)irectors' (iroup, Childrcen's Hospital, Shelficld S1) 2TH I Elliman 1), (iarnier J. Review of neonatal screening programme oter phenvilketonuria. BMI7 1991;303:471. (24 Atuguist. 2 Smith 1, Cook 13, 3easlev M. Re\iew of neonatal scrcening programme for phenylketonuria. RAU7 1991;303:333-5. i10 August.
Intravenous immunoglobulin and myalgic encephalomyelitis SIR,-In his editorial on intravenous immunoglobulin Dr A D B Webster calls for multicentre trials to assess the possible efficacy of this product in various conditions including mvalgic encephalomyelitis.' Two such placebo controlled trials have been completed. Unfortunately, the results are conflicting. American investigators treated their patients with 1 g/kg every month for six months.2 There were no obvious benefits when the treated patients were compared with controls given placebo. An Australian trial used an even higher dose of 2 g/kg over three months.' Here there were significant benefits in both physical and psychological wellbeing in the treatment group. In the United Kingdom this expensive form of speculative treatment is also being used by some doctors to treat myalgic encephalomyelitis. Before it joins the the ever growing list of treatments for this controversial condition it would seem sensible to discover whether there is a specific subgroup of patients who benefit and whether this is related to any characteristic defects in immune function. CHARLES SHEPHERD
Mledical Adviser, 1ME Association. Friars Cottage Surgery. Chalford Hill. Gloucestershire GL6 8EH I Wlebster ADB. Intravenous immtunoglobulins. Bktl 1991303: 375-6. i17 August. 2 Peterson PK. Shepard J. M\lacres M, Schenck C. Crosson J, Rechtman D, et al. A controlled trial of intravenous immunoglobulin G in chronic fatigue syndrome. Anjt Med 1990; 89:
554-60. 3 Lloyd A, Hickie I. Wakefield D. Boughton C, Dwver J. Intravenous immunoglobulin therapy in patients with chronic fatigue syndrome: a double-blind, placebo-controlled trial.
AtM37.1ed 1990;89:561-8.
Controlled trials in single subjects
importance.
Given the constant pressures of change and the numerous other demands on their time it is unrealistic to expect senior district staff, be they community paediatricians, public health physicians, or whatever, to undertake consistent long term monitoring of screening-and yet, as Drs Elliman and Garner say, someone has to take overall responsibility for ensuring that the system is working. In many areas it is the screening laboratory that has, to varying degrees and often very informally, assumed this responsibility. The laboratory is the central point in the process and has a continuous, consistent, and focused commitment to screening that is not found elsewhere in the svstem. The success or otherwise of screening laboratories in taking on this wider role is one of the factors behind the large variations in regional performance noted by I)r Isabel Smith and colleagues.' Perhaps it is time to formalise these activities bv broadening screening laboratory service agreements to include some form of continuing, district by district audit of collection and checking systems. Given the sensitive nature
SIR,-Dr Terje Johannessen forcefully argues the case for applying experimental methodology, using n of 1 trials, to the treatment of individual patients.' Some caution, however, is in order in interpreting and using the results of such trials. Take the case of the placebo controlled trial of cimetidine in non-ulcer dyspepsia reported in his figure 2. The diagram and description are ambiguous, but I interpret them to mean that some 25% of a group of patients studied responded to cimetidine, where response was defined as a p value of :0 2. (There was thus a rather disappointing overall rate of response.) If, however, the drug had exactly the same constant effect on every patient but patients' state of health varied at random from day to day we should, of course, expect that some n of 1 trials would show significant results and some would not. Furthermore, if we repeated the series of trials with the same patients some who previously showed a "significant" response would now fail to do so and vice versa. The fact, therefore, that some patients show a significant response in n of 1 trials whereas others BMJ
VOLUME 303
21 SEPTEMBER
1991
W5shlart J(G. Prenatal scrcintig for i)tons 2 g
4
5
h
tv n(iromre.
BAItJ7
1991;303:468-9. 24 Attgtist. e inpcratl\c cIaratcer *)ti ictdliacl I! nistri Ij]. j1i tchttlol)gt and the ntcaning ot ;aniticipatcd deitsiotn regret." lnt j chnoltl AssCss l1ltlth (Care 1989;:20)7Marteati T.1. tsYthological Implications ol' prenatal diagnosos. In: i)rile J(), i)ontalt 1), cds. Alnenatal dtagnosis of ftetal (Ibnortlltes. Ltondotn: Springer-Verlag, 1991. Larsson Gi Spatigherg L, Lintdgren 5, lioliliti 13. Screciing lor otl mImatcrrnal iptilotit. A111S HtI ill pregntant wotnci: aI SIldy (are 199(t;2:22;-s. McNeil 13J, l'autikecr SG, Sox [iCi, T vrskv A. (Ott tilt elititation tied of prelerenccs for alterinative tlteraptis. N 1 nogl1 19t12;306: 1259-62. Miarteau iTM. Fratitite} ol itiioriatioit: its ilfltiene u n dcc;s;oi1s of dcttors attd patents. fBr 7So PsYcholI19X9;28: 89-94.
Neonatal screening programme for phenylketonuria SIR,-In Dr Isabel Smith and colleagues' review of screening for phenylketonuria two unrelated points require comment.' Firstly, the authors incorrectly refer to the incidence of phenylketonuria when it was the prevalence at birth (or shortly after) that was determined. If a gene mutation is the cause of the phenvlketonuria onlv alterations in the mutation rate or the expression of the gene will affect the incidence of the condition. On the other hand, the prevalence at birth will also be affected by the duration of the condition, which is influenced by, for example, the rate of spontaneous abortion, and alterations in prevalence mav occur without there being any change in incidence. As it is not known how many affected fetuses are aborted it is not valid to equate incidence with prevalence. Secondly, on the basis that the number of tests exceeded the number of babies born the authors assume that population coverage was almost 100% and that the excess tests were repeat tests. This assumption may, however, be premature as many district health authorities do not link the result of the screening test to the birth notification. rhey therefore do not know either which or how many infants have not been tested. It is a simple expedient to develop administrative gutidelines that will ensure that the test result and birth notification are linked and to produce a weekly listing of those infants who have slipped the net to enable health visitors to chase them up. P 0 D PHAROAH
t)cpartmcnt otiCommu,nity Hcalth, tUniversity ot Liverpool. '() Box 147, Liverpool 1,69 3BX
Simith I1, (took B, Beaslev M. Review oi necoimatal scrcrleing programme for phlcilykctollUria. J3.MJ 1991,303:333-5. 10 Auiguist.
716
SIR.-In their review of the neonatal screening
programme for phenvlketonuria Dr Isabel Smith and colleagues report that the coverage of the programme is thought to approach 100lOO.' This figure is an estimate because of the inclusion of repeat tests but is supported by a recent review of the screening programme in North Hertfordshire Health Authority. This entailed matching results of laboratory tests to the district birth register for a three month cohort of births. Coverage of 98 3'%S was obtained according to the child health records, and this increased to 99-7'% after checks were made with the two screening laboratories concerned. This contrasts with the figure of 93 5'S obtained in an inner city district in the same region. TFhe local programme had no monitoring system to ensttre that a test result was received for every infant, and no one was responsible for coordinating the programme. We plan to improve the quality of the service delivered through the contracting process. KATE JOL.LY
North Hcrtlordshire Hcalth AuthoritV,
Hittlhin. HcIrtordshirc S(G5 IHF
Siiitith 1, (ook 13, B3caslev A. Rc\vicw ot nieoniatal screening programme for phenlivkctonuria. BAI7 1991;303:333-5. If) Aigtlst. 2 HLinter R, Roderick P, RLIta I), Sttiz-Stciger T. "fee)l tn heel"screetitg ot nm.wbtorn it Rterside tealith distritct hv Gtuthrn testetng. Loittdout: London Schotl ott Hvgiene and Tropical AMedicine, 1988.
SIR,-The finding by Drs David Elliman and June Garner that 2% of infants in their health district miss the neonatal screening tests for phenylketonuria and congenital hypothyroidism' indicates how difficult it can be to keep such programmes up to scratch. Their proposals to improve coverage are, however, unlikely in themselves to sustain the desired effect. Making Fhe health visitor responsible for ensuring that every babv in her case load had been tested did not work 30 years ago with the nappy test and is unlikely to do so now, whereas centralisation of both testing and checking procedures after the introduction of blood based screening in 1970 led to a considerable improvement in coverage. Screening samples are usually analysed in regional or subregional laboratories, while checking of negative results against birth lists is done at district level. Even this degree of decentralisation creates problems and in this and other regions we are increasingly experiencing instances where district based systems have broken down in the course of reorganisation or because of staff shortages. The checking itself is often delegated to relatively junior staff and those further up the hierarchy either do not notice that this task is no longer being performed or are unaware of its
of such undertakings there is an argument for maintaining a strong regional involvement in the provision of neonatal screening. RODNEY POLLITT Chairmani, UK Screccning laboratory I)irectors' (iroup, Childrcen's Hospital, Shelficld S1) 2TH I Elliman 1), (iarnier J. Review of neonatal screening programme oter phenvilketonuria. BMI7 1991;303:471. (24 Atuguist. 2 Smith 1, Cook 13, 3easlev M. Re\iew of neonatal scrcening programme for phenylketonuria. RAU7 1991;303:333-5. i10 August.
Intravenous immunoglobulin and myalgic encephalomyelitis SIR,-In his editorial on intravenous immunoglobulin Dr A D B Webster calls for multicentre trials to assess the possible efficacy of this product in various conditions including mvalgic encephalomyelitis.' Two such placebo controlled trials have been completed. Unfortunately, the results are conflicting. American investigators treated their patients with 1 g/kg every month for six months.2 There were no obvious benefits when the treated patients were compared with controls given placebo. An Australian trial used an even higher dose of 2 g/kg over three months.' Here there were significant benefits in both physical and psychological wellbeing in the treatment group. In the United Kingdom this expensive form of speculative treatment is also being used by some doctors to treat myalgic encephalomyelitis. Before it joins the the ever growing list of treatments for this controversial condition it would seem sensible to discover whether there is a specific subgroup of patients who benefit and whether this is related to any characteristic defects in immune function. CHARLES SHEPHERD
Mledical Adviser, 1ME Association. Friars Cottage Surgery. Chalford Hill. Gloucestershire GL6 8EH I Wlebster ADB. Intravenous immtunoglobulins. Bktl 1991303: 375-6. i17 August. 2 Peterson PK. Shepard J. M\lacres M, Schenck C. Crosson J, Rechtman D, et al. A controlled trial of intravenous immunoglobulin G in chronic fatigue syndrome. Anjt Med 1990; 89:
554-60. 3 Lloyd A, Hickie I. Wakefield D. Boughton C, Dwver J. Intravenous immunoglobulin therapy in patients with chronic fatigue syndrome: a double-blind, placebo-controlled trial.
AtM37.1ed 1990;89:561-8.
Controlled trials in single subjects
importance.
Given the constant pressures of change and the numerous other demands on their time it is unrealistic to expect senior district staff, be they community paediatricians, public health physicians, or whatever, to undertake consistent long term monitoring of screening-and yet, as Drs Elliman and Garner say, someone has to take overall responsibility for ensuring that the system is working. In many areas it is the screening laboratory that has, to varying degrees and often very informally, assumed this responsibility. The laboratory is the central point in the process and has a continuous, consistent, and focused commitment to screening that is not found elsewhere in the svstem. The success or otherwise of screening laboratories in taking on this wider role is one of the factors behind the large variations in regional performance noted by I)r Isabel Smith and colleagues.' Perhaps it is time to formalise these activities bv broadening screening laboratory service agreements to include some form of continuing, district by district audit of collection and checking systems. Given the sensitive nature
SIR,-Dr Terje Johannessen forcefully argues the case for applying experimental methodology, using n of 1 trials, to the treatment of individual patients.' Some caution, however, is in order in interpreting and using the results of such trials. Take the case of the placebo controlled trial of cimetidine in non-ulcer dyspepsia reported in his figure 2. The diagram and description are ambiguous, but I interpret them to mean that some 25% of a group of patients studied responded to cimetidine, where response was defined as a p value of :0 2. (There was thus a rather disappointing overall rate of response.) If, however, the drug had exactly the same constant effect on every patient but patients' state of health varied at random from day to day we should, of course, expect that some n of 1 trials would show significant results and some would not. Furthermore, if we repeated the series of trials with the same patients some who previously showed a "significant" response would now fail to do so and vice versa. The fact, therefore, that some patients show a significant response in n of 1 trials whereas others BMJ
VOLUME 303
21 SEPTEMBER
1991
