801

We than evaluated a booster dose of either vaccine allocatedrandomly within initial vaccine groups and administered at age 1year or so. For polio types 1, 2, and 3 the boost achieved by the Salkvaccine was consistently better than the boost achieved with oralvaccine, irrespective of the initial vaccine given, although notsignificantly so for antibody levels to polio 2.These results confirm previous findings from Africa showing

that oral poliovaccine fails to achieve seroconversion in a significantproportion of children. 19% of Gambian infants given three dosesof oral vaccine had polio type 1 antibody titres below 1:10. No childin this study contracted paralytic poliomyelitis but some of themmay have been unprotected and susceptible to challenge with a wildtype 1 virus. During the 1986 epidemic several clinical cases werefound to have been fully vaccinated (Denning M, personalcommunication).A booster dose of intramuscular vaccine was more successful than

an oral booster. Provided a very high coverage rate can be achieved abooster dose of killed poliovaccine might be more effective than afurther dose of oral vaccine in stopping an epidemic of the typeexperienced in The Gambia.

Medical Research Council Laboratories,PO Box 273,Banjul, The Gambia;

and Tropical Epidemiology Unit,London School of Hygieneand Tropical Medicine,

London WC1

P. HANLONL. HANLONV. MARSHP. BYASSH. SILLAHR. HAYESH. C. WHITTLEB. M. GREENWOOD

1. Editorial. Polio reconsidered. Lancet 1984; ii: 1309-10.2. John TJ. Poliomyelitis in India: Prospects and problems in control. Rev Infect Dis

1984; 6: 438-41.

STATISTICAL ANALYSIS OF LIPID RESEARCHCLINICS PROGRAM

SiR,—The letter from Dr Pinckney and Dr Smith (Feb 28,p 503) contains erroneous and misleading statements about theLipid Research Clinics (LRC) Coronary Primary Prevention Trial(CPPT).1 Without reopening the debate on statistical issues that wehave addressed previously at length,2 we would like to respond onthe following points.

(1) In their initial paragraph, Pinckney and Smith cite a 1984Lancet editorial3 as advising two-tailed testing for all drug trials, andwonder how this position can be reconciled with The Lancet’sendorsement of the CPPT’s conclusion that lowering raisedcholesterol levels reduces the risk of coronary heart disease (CHD).That editorial distinguishes between trials aimed at testing "ascientific hypothesis" (eg, the so-called cholesterol hypothesis,relating reductions in plasma cholesterol levels and CHD risk) andtrials aimed at "evaluating a therapy," and acknowledges theappropriateness of a one-tailed test in the former category. Since theCPPT was designed as a test of the cholesterol hypothesis and usedcholestyramine therapy only as the most feasible way to obtain thenecessary reduction in cholesterol levels,4 the editorial does notcontradict itself.

(2) In their next paragraph, Pinckney and Smith recite a series ofallegations concerning manipulation of the data analysis so that theCPPT outcome would appear more favourable than it was. We willnot respond here to their allegations concerning significance testing;our position on these issues, as explained elsewhere2 in great detail,has not changed. However, their statement that "the project becamea drug study, not a diet study" (and the implication that this wassomehow improper) requires a response. This statement was basedon part of a sentence taken from the first page of the 1984 CPPTresults paper’ (the 1979 CPPT design paper was incorrectly given asthe source): "the most appropriate trial of the efficacy of cholesterollowering would be a dietary study". Pinckney and Smith shouldhave pointed out that the paper went on to say: "However, the 1971National Heart and Lung Institute Task Force on Arteriosclerosisrecommended against conducting a large-scale, national diet-hearttrial in the general population, because of concern regarding theblinding of such a study, the large sample size and the prohibitivecost... Accordingly, the LRC-CPPT was initiated in 1973 as an

alternative test of the efficacy of reducing cholesterol levels ... Theuse of the drug cholestyramine resin permitted a double-blinddesign".1 Thus, the CPPTfrom its outset used cholestyramine as themeans for attaining a plasma cholesterol differential betweenrandomised treatment groups.

(3) Next, Pinckney and Smith incorrectly state that the excess ofgastrointestinal cancers in the cholestyramine group was

"significant, by conventional satistical tests". We reported in 1984that there were 21 such cancers (6 buccal cavity/pharynx, 2oesophagus, 6 colon, 4 rectum, 3 pancreas) in the cholestyraminegroup and 11 (1 oesophagus, 2 stomach, 6 colon, 2 rectum) in theplacebo group.’ Setting aside the question of whether conventionalstatistical tests are appropriate when such pathologically disparatecancers are grouped post hoc, the conventional statistical test for afour-fold table gives X2 = 3 (2-5 if the continuity correction is used),Although this result was not significant at the p = 0-05 level, it wasnot merely "brushed aside". Whereas Pinckney and Smith allegethat "the investigators had nothing to say about this observation intheir reports", the 1984 CPPT results paper indicates otherwise:"The small numbers and the multiple categories preventconclusions being drawn. However, in view of the fact that

cholestyramine resin is confmed to the GI tract and not absorbedand of animal experiments in which cholestyramine resin has beenfound to be a promoter of colon cancer when a cancer inducingagent was also fed orally, further follow-up of the LRC-CPPTparticipants is planned for cause-specific mortality and cancermorbidity".’ This follow-up study is now in progress.

(4) Finally, Pinckney and Smith state that "In response to manycritical [of the CPPT] letters ... a J AMA editorial essentiallyadmitted that the study was improperly analysed". That editorial,published 1 years after the CPPT results (vol 253, not 293), is ageneral article on statistical review and does not comment, evenindirectly, on the statistical analysis (or any other aspect) of theCPPT. We are at a loss to see how this article can be construed as aneditorial disclaimer of the CPPT.We suggest that the readers of The Lancet refer directly to the

CPPT reports and to the other sources cited by Pinckney andSmith, rather than accept at face value their representation of whatthese sources say, before drawing their own conclusions. We areconfident that most will conclude, as did the 1984 AmericanConsensus Conference on Lowering Blood Cholesterol to PreventHeart Disease, that "It has been established beyond any reasonabledoubt that lowering definitely elevated blood cholesterol levels(specifically blood levels of low-density lipoprotein cholesterol) willreduce the risk of heart attacks due to coronary heart disease".6

National Heart, Lungand Blood Institute,

Bethesda, Maryland 20892, USALIPID RESEARCH CLINICSPROGRAM INVESTIGATORS

1. The Lipid Research Clinics Program The Lipid Research Clinics Coronary PrimaryPrevention Trial Results I: Reduction in incidence of coronary heart disease.

JAMA 1984; 251: 351-64.2. The Lipid Research Clinics Program. Reply to commentary by Richard Kronmal.

JAMA 1985; 254: 263-64.3. Editorial. Is reduction of blood cholesterol effective? Lancet 1984; i 317-184. The Lipid Research Clinics Program. The Coronary Primary Prevention Trial:

Design and implementation. J Chron Dis 1979; 32: 609-31.5. Vaisrub N. Manuscript review from a statistician’s perspective. JAMA 1985; 253:

3145-47.

6. Consensus Conference. Lowering cholesterol to prevent heart disease. JAMA 1985;253: 2080-90.

TETANUS AND ALTITUDE

SIR,-An apparent absence of clinical tetanus has been noted invisits to Zanskar and Ladakh in recent years. These are both areas inthe Himalayas at altitudes above 3000 m. Hygiene is generally poor;horse, cow, and yak dung plentiful; trauma is common in theseagricultural communities; and infants are traditionally nursed indiapers of powdered sheep dung-all features which should favourthe disease. Yet tetanus, especially in the newborn, which is verycommon in other parts of India has not been found.

Failure of diagnosis is unlikely to be the explanation. Ladakhidoctors are trained in Kashmir or in medical schools south of the

Himalayas, where tetanus is a common condition and they wouldtherefore easily recognise cases. Both adult and neonatal tetanus are