To the Editor: In their study on the use of florbetapir for positron emission tomographic (PET) imaging of brain β-amyloid,1 Dr Clark and colleagues submitted to JAMA median values for PET scan reader scores but withheld critical individual reader score data that Avid Radiopharmaceuticals submitted to the Food and Drug Administration (FDA) on September 17, 2010. FDA analyses of these data show substantial interreader variability among independent, extensively trained readers of the florbetapir-PET scans for individuals in the autopsy cohort,2 emphasizing that florbetapir-PET imaging fails to provide an accurate and reliable assessment of amyloid burden.
The primary end point for the autopsy cohort was the correlation between the amyloid burden in the brain as measured by florbetapir-PET, using a prespecified semiquantitative visual rating scale (0-4) and cortical amyloid burden by pathology using quantitative immunohistochemistry. The published measurement of the amyloid burden for this correlation was the median rating of 3 expert independent readers who underwent extensive training, a process that the authors acknowledged “is not likely to be replicated in clinical settings.”1 Therefore, data on the interreader variability for the 3 independent readers is crucial to evaluating the potential clinical utility of florbetapir-PET.
Independent FDA analysis of the data regarding florbetapir-PET scoring by the individual readers for the 35 individuals who underwent autopsy revealed substantial inconsistency among the readers, with sensitivities of 55% (95% confidence interval [CI], 28%-79%), 85% (95% CI, 64%-95%), and 90% (95% CI, 69%-97%) and specificities of 80% (95% CI, 55%-93%), 100% (95% CI, 82%-100%), and 100% (95% CI, 86%-100%).2 This analysis assumed that a semiquantitative score of 0 or 1 was a negative test and a score of 2 to 4 was a positive test, consistent with the authors' approach.
In 8 of 20 participants in the autopsy cohort (40%) who had positive immunohistochemistry for amyloid, at least 1 reader's scoring of the florbetapir-PET scans differed from that of the other 2 readers by 2 or 3 points on the 5-point scale.3
The study implemented florbetapir-PET in a rigorously controlled setting with well-trained readers, using patient populations at 2 extremes of the spectra for both age and health. However, despite these optimal conditions, the test yielded disparate results when looking at the analysis of the individual readers. If widely deployed in the real-world setting, with more variability in reader training and skill and in the patient population for whom florbetapir-PET presumably is intended, the performance of the test will most likely be worse. For these reasons, in our opinion the FDA should not approve florbetapir for diagnosis of Alzheimer disease.
Conflict of Interest Disclosures: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal
Instructions
Comments are moderated and will appear on the site at the discretion of the Journal of American Medical Association editors. Comments should not exceed 500 words of text and 10 references.
Do not submit personal medical questions or information that could identify a specific patient, questions about a particular case, or general inquiries to an author. Only content that has not been published, posted, or submitted elsewhere should be submitted. By submitting this Comment, you and any coauthors transfer copyright to the journal if your Comment is posted.
* = Required Field
Disclosure of Any Conflicts of Interest* Indicate all relevant conflicts of interest of each author below, including all relevant financial interests, activities, and relationships within the past 3 years including, but not limited to, employment, affiliation, grants or funding, consultancies, honoraria or payment, speakers’ bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued. If all authors have none, check "No potential conflicts or relevant financial interests" in the box below. Please also indicate any funding received in support of this work. The information will be posted with your response.
Register and get free email Table of Contents alerts, saved searches, PowerPoint downloads, CME quizzes, and more
Subscribe for full-text access to content from 1998 forward and a host of useful features
Activate your current subscription (AMA members and current subscribers)
Some tools below are only available to our subscribers or users with an online account.
Download citation file:
Customize your page view by dragging & repositioning the boxes below.
and access these and other features:
Register Now
Enter your username and email address. We'll send you a reminder to the email address on record.
Athens and Shibboleth are access management services that provide single sign-on to protected resources. They replace the multiple user names and passwords necessary to access subscription-based content with a single user name and password that can be entered once per session. It operates independently of a user's location or IP address. If your institution uses Athens or Shibboleth authentication, please contact your site administrator to receive your user name and password.