REAL-PET and CONSORTPaul K. Morrish, DM

The study presented by Whone and colleagues1 is method-ologically and ethically flawed and should not have beenpublished in a journal upholding CONSORT2 guidelines.

[18F]dopa PET scans were carried out at six different cen-tres and the data analysed locally before central analysis.Prior to central analysis, the study result did not reach sig-nificance3. Central analysis included the removal of 11% ofthe results because the first PET scan was normal. The resultthen reached significance. The timing of the decision to re-move these results is not clear. We read that “ a decision wastaken, prospectively, to include only patients with PET evidenceof PD” but the published study design fails to mention this4.The ethics of treating and rescanning 11% of patients, yetprospectively excluding their data from the trial, is question-able.

There is, furthermore, no scientific validity in the deci-sion. [18F]dopa PET does not completely discriminate PDfrom normality at symptom onset 5. Figures for symptomaticthreshold (75% of normal) and distribution in normal range(SD 14%) from work with 2D PET 6 give the positive andnegative predictive value of PET scans. If the study popula-tion has 90% PD and 10% normal subjects, the negativepredictive value (the chance of being disease free after a nor-mal scan) is only 16%. 3D PET might be different but theinformation needed to make that calculation has not beenprovided.

I question the decision to publish the paper in this form.Schulz2, in his introduction to CONSORT, stated that anal-ysis should include “all properly randomised participants in theoriginally assigned groups”. The data could have been pub-lished with and without the removal of the cohort of PDpatients so that its effect could clearly be seen.

Hurstwood Park Neuroscience Centre, Princess Royal Hospital,West Sussex, United Kingdom

References1. Whone AL, Watts RL, Stoessl AJ et al. Slower Progression of

Parkinson’s Disease with Ropinirole versus Levodopa: TheREAL-PET Study. Ann Neurol 2003;54:93-101.

2. Schulz KF. The quest for unbiased research: randomized clinicaltrials and the CONSORT reporting guidelines. Ann Neurol.1997 ;41(5):569-73.

3. Whone AL, Remy P, Davis MR et al. The REAL-PET Study:Slower Progression in Early Parkinson’s Disease Treated withRopinirole Compared with L-Dopa. Neurology 2002:58:7(S3);A83.

4. Brooks DJ. Design and Demography of a Double-Blind Trial toInvestigate Possible Neuroprotective Effects of Ropinirole vsL-Dopa with 3D[18F]-Dopa PET Scanning. J Neurol Sci 2001;187 (S1); S239.

5. Morrish PK, Sawle GV, Brooks DJ. Clinical and [18F] dopaPET findings in early Parkinson’s disease. J Neurol NeurosurgPsychiatry. 1995 Dec;59(6):597-600.

6. Morrish PK, Rakshi JS, Bailey DL et al. Measuring the rate ofprogression and estimating the preclinical period of Parkinson’sdisease with [18F]dopa PET. J Neurol Neurosurg Psychiatry.1998 Mar;64(3):314-9.

DOI: 10.1002/ana.10774

ReplyDavid J. Brooks, MD, and Alan L. Whone, MRCP

Dr. Morrish’s five concerns are addressed in order.First, he states that the positron emission tomography

(PET) data acquired at six centers was analyzed both locallyand centrally and that the result of the local analysis, whichdid not reach significance, was known ahead of the centralanalysis being performed. This last statement is incorrect;only after all blinded Ki data were collected, both locally andcentrally, were predefined statistical tests applied. Hence, re-sults of one analysis did not influence the conduct of an-other. Methodology for performing a centralized analysiswith spatial normalization was only developed during thecourse of this trial, once this methodology was available itwas determined ahead of analysis that a centralized approachwould provide the primary imaging end point. This was be-cause local analyses did not involve spatial normalization andvaried in methodology. The combined local analysis, whichhas been presented in abstract,1 was not presented in ourmanuscript as we were reporting only our primary imagingoutcomes. However, if a Hochberg adjustment is applied totake account of the three analysis methods (local region ofinterest [ROI]), central ROI, and central statistical paramet-ric mapping [SPM], the central ROI analysis and SPM find-ings remain significant. The “published study design” thatDr. Morrish references is an abstract reporting the aims ofthe study and numbers of patients randomized and providesno details on how PET analysis was to be performed.

Second, Dr. Morrish questions the timing of the removalof subjects with normal scans, the suggestion being that thiswas done after first examining endpoints with these subjectsincluded. This is incorrect—during blinded centralized ROIanalysis of the baseline PET data acquired at our center(Hammersmith), which was analyzed ahead of other centersand predominantly during the last year of the study, it wasseen that 5/34 (15%) subjects had normal baseline PET im-aging. It was acknowledged that if a similar discordance be-tween clinical diagnosis and PET findings was seen across allcenters, at our given statistical power, the outcome measurewould be biased if more subjects with “normal” PET scansby chance fell into one treatment group or another. More-over, it was recognized that the primary endpoint was imag-ing rather than clinical and we wished to only include sub-jects in the efficacy analysis where changes in the biomarkerwould be evident over two years. Consequently, at an inves-tigator meeting it was decided a priori that subjects with nor-mal baseline PET would be excluded from our primary out-come measure i.e. before database closure, unblinding andstatistical analysis. In a post hoc analysis of the data whensubjects with normal imaging were included SPM continuedto show significant progression differences between treat-ments. Follow-up imaging in the patients with normal base-line scans showed no change over 2 years, which in part val-idates our decision to remove these subjects.

Third, Morrish states that treating and rescanning subjectswith normal baseline scans was unethical. This is not so, thediagnosis of Parkinson’s disease remains clinical and 18F-dopaPET is not a licensed diagnostic tool. Further, as stated in ourmanuscript,2 we do not yet know what this clinical/PET dis-

LETTERS

692 © 2003 American Neurological AssociationPublished by Wiley-Liss, Inc., through Wiley Subscription Services

cordance means and we are pursuing a study to answer thisquestion. As the central analysis was performed during the lastyear of the study the 21 subjects with normal scans were notidentified until near the end of the trial, however, the clini-cians responsible for these patients have been informed.

Fourth, Dr. Morrish’s study on the discriminating power of2D-PET is out of date.3 The separation between normal andabnormal imaging using high resolution high sensitivity 3D18F-dopa-PET is complete in contrast to his 1995 report and,using the method outlined in our manuscript, 3 investigatorswere independently able to separate the 21 “normal images”with 100% concordance.2 However, to validate that these sub-jects indeed had normal nigrostriatal pathways and that thePET images were “correct” we would need post-mortem data.

Finally, the last statement relating to the CONSORTguidelines is incorrect.4 In the Schultz special report a prin-cipal concern related to authors failing to report that exclu-sions had been made post randomization, this is clearly notthe case in our manuscript. Indeed, in line with CONSORTguidelines we went to great lengths to detail how, when, andwhy exclusions of subjects with normal scans were made.

MRC Cyclotron Unit, Hammersmith Hospital, Royal PostgradMedical School, London, United Kingdom

References1. Whone AL RP, Davis MR, Sabolek M, Nahmias C, Stoessl AJ,

Watts RL, Brooks DJ. The REAL-PET study: Slower progres-sion in early Parkinson’s disease treated with ropinirole comparedwith L-dopa. Neurology. 2002;58(7):A82–A83.

2. Whone AL, Watts RL, Stoessl AJ, et al. Slower progression ofParkinson’s disease with ropinirole versus levodopa: The REAL-PET study. Ann Neurol 2003;54:93–101.

3. Morrish PK, Sawle GV, Brooks DJ. Clinical and [18F] dopa PETfindings in early Parkinson’s disease. J Neurol Neurosurg Psychi-atry 1995;59:597–600.

4. Schulz KF. The quest for unbiased research: randomized clinicaltrials and the CONSORT reporting guidelines. Ann Neurol1997;41:569–573.

DOI: 10.1002/ana.10773

CorrectionsMarder K, Levy G, Louis ED, Mejia-Santana H,Cote L, Andrews H, Harris J, Waters C, Ford B,Frucht S, Fahn S, Ottman R. Familial aggregationof early- and late-onset Parkinson’s disease. AnnNeurol 2003;54:507–513.

Due to an oversight, there were errors in Tables 1–3of the above mentioned article. The corrected informa-tion is listed below:

Table 1:In column 2, line 4, the standard deviation for ed-

ucation of early-onset probands is listed incorrectly as“3–4”. The correct SD is 3.4.

The superscript notes in the Table 1 footnote shouldread:

Comparison between early- and late-onset PDprobands, ap<0.001.

Comparison between total PD probands and con-trol probands, bp<0.001; cp<0.05.

“NA � not applicable” is repeated in the footnote;please disregard the second mention.

Table 2:The superscript notes in the Table 2 footnote should

read:Comparison between relatives of early- and late-

onset PD probands, ap<0.001.Comparison between relatives of total PD pro-

bands and control probands, bp<0.001.

Table 3:In the fourth column, last row: “1.0 (reference)”

should be listed instead of “1 (reference)”.The corrected tables can be viewed online at www.

interscience.wiley.com, DOI: 10.1002/ana.10778

DOI: 10.1002/ana.10778

Han X, Fagan AM, Cheng H, Morris JC, Xiong C,Holtzman DM. Cerebrospinal fluid sulfatide is de-creased in subjects with incipient dementia. AnnNeurol 2003;54:115–119.

In Figure 2D, values of pTau231 were reported onthe Y-axis. This was done from a commercial kit froma company called “Innogenetics”. The error was thatthe authors actually measured pTau181P. The valueslisted are all correct, but the Y-Axis should readpTau181P. Please also note this corrected value in thefollowing sections of the article: Methods (page 116,second column, first paragraph; pTau231 should bepTau181P) and in the Figure 2D, legend (pTau231should be pTau181P).

DOI: 10.1002/ana.10819

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