One of the bigger mishaps was that from the beginning of the study through March of 2007, some sites collected CSF samples into polystyrene tubes. Aβ sticks to this plastic, and use of those tubes has been shown to falsely lower CSF Aβ measurement by up to a third, according to Cindy Carlsson at the University of Wisconsin ADNI site. Carlsson, a geriatrician who conducts trials using CSF markers as outcome measures, discovered that the sterile CSF collection tubes in the ADNI lumbar puncture kits sent through a contract research organization were made of polystyrene. ADNI had provided each site with the polypropylene tubes needed for storing Aβ properly, but they were not sterile; hence, sites using a CSF drip technique that requires sterile tubes ended up using the wrong plastic. Carlsson added that ADNI fixed this problem as soon as it became apparent. When asked how many samples were affected, Shaw e-mailed to ARF: “We studied this very carefully, including by directly comparing CSF collected in polypropylene tubes to CSF collected in polystyrene tubes that are included in the standard lumbar puncture tray, and using an exposure time that most closely mimicked that for ADNI collections. We saw only minor decreases in Aβ42 and tau, none in P-tau, and hardly detectable [change] in the tau/Aβ42 ratio. This important issue was not a likely contributor to significant variability in our study.”
A second hiccup occurred around shipping logistics. It highlights the need for planning operating procedures down to minute details in such a large and complex study. The 58 local ADNI sites ship blood samples to the National Cell Repository for Alzheimer’s Disease (NCRAD), where the staff establishes cell lines for genetic studies on ADNI participants. According to NCRAD's principal coordinator Kelley Faber, ADNI samples often arrived at NCRAD on Saturdays, when NCRAD is closed. This might have been because participating sites ship some samples to NCRAD and others to the biomarker core at UPenn, which does receive shipments on Saturdays. On Saturdays, the ADNI boxes destined for NCRAD then got dropped off at a different lab at Indiana University. Not being part of the cell repository, that lab often refrigerated the samples, which is detrimental to the growth of the cell lines, Faber wrote to ARF. The NCRAD staff repeatedly instructed ADNI sites to hold samples drawn on Friday at room temperature and ship them on Monday, and also asked their local colleagues to store the Saturday arrivals correctly until Monday. The problem occurs less often now but, due to staff turnover in all those different labs, has not gone away. Were samples lost? “I don’t think many, if any, were lost, as we tried to give them extra TLC,” Faber wrote.
Moreover, samples sometimes arrive unaccompanied by their requisite form. This can be a major issue because the NCRAD staff then cannot easily double-check identifying information on the tubes. At other times, urine or CSF arrived at NCRAD instead of UPenn and had to be forwarded there. Overall, however, Faber noted that ADNI is going well. “Everyone was always friendly and willing to work together. The main issue was due to the number of sites and people working on the project. A lot has been learned from the ADNI study and will be used to improve future studies,” Faber concluded. Tatiana Foroud of NCRAD concurred that ADNI is going smoothly given its size and complexity. “We were very pleased to be a part of the ADNI project,” said Foroud.
Several scientists interviewed for this article regretted the timing of ADNI’s PIB-PET substudy. When the original ADNI grant was written in response to the request for applications the NIA had issued in October 2003, amyloid imaging was generating buzz at conferences and initial human data had been published (Engler et al., First human study with a benzothiazole amyloid-imaging agent in Alzheimer’s disease and control subjects. Neurobiol Aging. 2002;23 suppl 1:S429). But PIB was not formally ready for prime time, because the first widely noticed paper appeared in March 2004 (Klunk et al., 2004).
By the time ADNI’s amyloid imaging substudy was funded and set to go, ADNI had already enrolled so many participants that the substudy had to accept people who had undergone baseline FDG and MRI scans a year before, according to Chet Mathis of University of Pittsburgh School of Medicine. This cut into its ability to obtain three consecutive longitudinal scans on normal control and MCI volunteers, and to compare that side-by-side with ADNI’s other assessments. “We wish we had started sooner,” Mathis wrote to ARF. On the upside, the study made up the lost scans by enrolling more people than originally planned.
Finally, some scientists privately shared a concern that frequently accompanies big distributed science consortia beyond AD research. While they expect that ADNI will achieve its primary goals, they also say that it will necessarily do so at a low common denominator in terms of data quality. This concerns, for example, imaging resolution. That is because ADNI, despite everyone’s best efforts at standardization, must still absorb a considerable degree of remaining site variation. A related concern voiced privately is that ADNI may create the impression that the big problems are solved. In the process, it absorbs a large chunk of the available funding at the expense of more technically innovative, cutting-edge imaging and biomarker research in individual labs that might pay off later. That said, all sources agreed that the field has to have multisite data to move forward.
In most interviews, talk about fumbles and compromises came as part of a larger sense that overall, ADNI has worked surprisingly well. The problems underscore how daunting a task it has been to coordinate such a large undertaking, and how many obstacles had to be overcome. Here’s Sterling Johnson, co-principal investigator with Sanjay Asthana of the University of Wisconsin site. “There has been a high degree of planning, thoroughness, and standardization on every aspect of the complex data collection protocol.”—Gabrielle Strobel.
This is Part 5 of a six-part series. See also Parts 1, 2, 3, 4, 6. Read the entire series [.pdf].