Early in the design phase of the SIT Trial, the acquisition from sites and distribution to the radiology panel of hard copy film was determined to be too costly and too slow. An electronic distribution and reporting system was the obvious solution. However, the challenge was to design a process that took advantage of available technology that could be economically adapted for multi-institutional research use. In addition, because the MRI studies serve as a key element in screening potential subjects for the SIT Trial, not only was a thorough interpretation required, but the findings needed to be disseminated quickly in order to transition the eligible participants into the randomization phase of the trial.

Figure ​Figure11 displays the technology and workflow implemented by the ERL to support the SIT Trial. Initially, the ERL provided each of the 28 participant enrolling sites (United States, Canada, United Kingdom and France) with two software programs to transmit the MRI images electronically to the imaging center at Washington University in St. Louis. The first program was the commercially available VPN Client (Cisco Systems, San Jose, CA, USA). This software creates a secure virtual private network between a sending and receiving site which allows the images to be sent encrypted over the internet.

The second software program was the Clinical Studies Workstation (CSW) program. CSW is a Windows (Microsoft, Redmond, WA, USA) program that was previously developed by ERL to transmit images for clinical trials. This software allows site personnel to receive DICOM studies directly from a local modality/PACS or a CD-ROM. CSW also provides a graphical user interface with which site personnel can remove Protected Health Information (PHI) and replace it with unique study identifiers, and then transmit the study to a DICOM receiver over the internet using a secure VPN connection. CSW was chosen for the SIT Trial over other competing products because it is easier to support remotely and has an ideal balance between the functionality required for the project and the technical abilities of the users at the clinical sites. In addition CSW is a well-tested software package that incorporates a de-identification algorithm that has been successfully applied in two previous major clinical trials^11–13 and which is conformant to the DICOM committee recommendation for de-identification of DICOM objects.¹⁴ Figure ​Figure22 is an example of the CSW program showing how the PHI is replaced with the participant identifiers.

The enrollment sites were provided with a laptop computer with the VPN Client and Clinical Studies Workstation software preinstalled. The laptop provides the portability required at many sites which collect MRI images from an MRI scanner or PACS located on the hospital network but later transmit the images by site study personnel while attached to a university or research network. Some sites had sufficient personal computer resources that required only the installation of the VPN Client and CSW programs.

Site personnel were trained on both the VPN Client and CSW programs. The sites use a variety of personnel to transmit the images, MRI technologists, PACS administrators, Radiology Department IT support, or study coordinators (clinical nurses). An operations manual provides detailed instructions for transmitting MRI studies and troubleshooting software and network problems. Because of frequent turnover in site personnel a web-based conference call training session was also developed to orient new personnel.

The imaging center data analysts use a web-based system to register the participant in the database and to upload studies to the image viewing system. An automated telephone response registration system, managed by the Data Coordinating Center, is used by the clinical sites to register participants for the SIT Trial. After the required registration information has been provided by the site study coordinator via telephone, the automated telephone response system automatically faxes the assigned participant code and identification number to the imaging center. The assigned participant code and identification numbers are then entered into the imaging database through the web interface. Next, the registration form is compared to the Image Tracking Worksheet and the transmitted images file. If the identifiers match, the data analysts execute an upload command and a check-in screen is presented that displays the details of a study. Figure ​Figure33 is an example of a check-in screen. This check-in screen is used to both process the study before it is entered into the image database and to upload to the image viewing system. The check-in process begins by obtaining a unique accession number which is used to identify the study in both the database and the image viewing system. Next, an exam type is selected which later will determine what series of case report forms (CRFs) are generated. Then the study is assigned to the “on-call” radiologist who reviews each study in less than 24 h to assess for any routine or urgent incidental findings.

The table of series parameters in Figure ​Figure33 serves two functions. First, it allows the data analysts to conduct a QA review to ensure that the number of images received matches the number indicated on the faxed Image Tracking Worksheet and to ensure that the pulse sequences submitted meet the imaging protocol requirements. Second, the data analysts select a common Protocol Code description and appropriate image plane for each series. This information is collected in the image database and helps facilitate data mining for ancillary studies.

The workflow imbedded in the check-in program automatically triggers the next step of the process, the automated upload of the study to the image viewing system. The QA process on the image viewing system ensures the participant’s study can be located by patient identifier or accession number. This process also ensures that previous MRI studies for this participant are presented together. The MRI study images are then checked to make sure all Protected Health Information (PHI) has been removed. Next the number of series and images is checked to ensure the upload was successful. The image quality assurance steps evaluate the MRI study for adherence with the imaging protocol, confirm images cover the entire brain, and determine if obscuring artifacts are present. If all QA checks are passed, the study is ready for viewing by the radiology panel.

The last part of the check-in process consists of email notifications. After a study or group of studies has been processed, the neuroradiologists are notified that new studies have been added to their web-based work list. This eliminates the need for the neuroradiologists to disrupt their daily activities and connect to the web site just to see if there is new work. This also allows the imaging center to provide any special instructions to the radiologists. In addition, the clinical site is notified that their study has been received and processing has begun. This step provides reassurance to site personnel that the transmission process is complete and establishes a time frame for when they should expect to receive the results.

For the SIT Trial, we have implemented two types of monitor calibration procedures. In these procedures controls were set to take full advantage of the display’s capabilities to achieve set minimum and maximum luminance targets. During deployment and setup of the radiology viewing workstations, our goal was to maximize the performance of the particular display model for the reading environment used by each neuroradiologist. The deployment calibration procedure required a photometer with a “field of view” or “angle of acceptance” in the 8° to 15° range. For the SIT Trial, we used an UDT Instruments (San Diego, CA, USA) Model 371 Meter with a Model 265 Probe, which comes with a photopic filter and an occluder to keep out the ambient light. During the calibration, luminance adjustments were made with the backlight, contrast, and brightness controls on the monitor to achieve the specified luminance values while viewing a series of test patterns.

Given the observations that monitor performance changes with time, the second calibration procedure used in the SIT Trial provided a method to set a display’s controls so that its performance continued to match the specified luminance targets. The ERL staff or radiologists perform a quarterly calibration check that requires only a few minutes of their time. Should the monitor fail this simple test, the monitor will be recalibrated by ERL staff using the same procedures as the deployment calibration. The quarterly check consists of viewing the test pattern in Figure ​Figure66 to determine if the “0” square, upper left, is totally black and the “255” square, lower right, is totally white. The interior squares in the “2” and “250” squares may be visible; however, the interior squares in all of the other boxes of the top and bottom lines should be visible.

The neuroradiologists use the iSite image viewing system to view the images and the web-based Case Report Form system to record their findings. The review process starts with the neuroradiologists being notified via email that a new study has been added to their worklist. Each radiologist accesses the web site to view a worklist similar to the one presented in Figure ​Figure7.7. The worklist provides the radiologist the accession number that can be used in iSite/Radiology to retrieve the study.

After viewing the study in iSite, the radiologist can click on the CRF in the Form No. column and be taken to the web-based CRF for that study. Figure ​Figure88 is an example of the CRF completed by the “on-call” radiologist after the initial assessment for incidental findings. Completing the form is very quick, only requiring the radiologist to make one selection and save the results. This information is automatically entered into the imaging database. Because the radiologists are blinded to the actual subject demographics, any specific incidental findings are communicated to the Clinical Coordinating Center staff.

The radiology committee conducts a biweekly conference call to review each study. For each study, the radiologist assigned as the “on-call” radiologist for that study is designated as the recording radiologist for that particular study. This radiologist will have on their worklist a CRF that is similar to Figure ​Figure11.11. This CRF displays the findings of each radiologist along with the ability to indicate a consensus lesion assessment. A consensus presentation state is also created in iSite which shows the location and size of the lesion(s). Studies with discordant interpretations are reviewed in depth. Quality failures are also discussed and clinical sites notified of specific problems.

Several imaging time points require the collection of lesion measurement data. Although all of the radiologists participate in determining the lesion size, for consistency in reporting, the chairman of the radiology committee has been designated as the recorder of the measurement data. Figure ​Figure1212 is an example of the web-based CRF used to collect measurement data. The participant identifiers and exam particulars ensure that the CRF matches the study being read. Although this CRF collects a large amount of data, it is designed to minimize the workload for the radiologist. The form is populated with an input column based on the number of lesions found. Radio buttons and check boxes are provided to facilitate entering the data. Text boxes are also provided to capture any additional information.

Substantial contributions to the study were also made by individual members from the following SIT Trial committees: Executive Committee—Michael R. DeBaun, MD, MPH (Chair, Co PI for the SIT Trial), Washington University in St. Louis School of Medicine, Bruce Barton, PhD, (PI for the Statistical Coordinating Center) Maryland Medical Research Institute, Inc., James F. Casella, MD (Vice-Chair and Co-PI for the SIT Trial), Johns Hopkins University School of Medicine, Deborah Hirtz, MD, National Institute of Neurological Disorders and Stroke, Rebecca N. Ichord, MD, Children’s Hospital of Philadelphia, Robert C. McKinstry, MD, PhD, Michael Noetzel, MD, Washington University School of Medicine, Fred Prior, PhD, Mallinckrodt Institute of Radiology, Washington University, and Desiree A. White, PhD, Washington University. Neuropsychology Committee—Desiree A. White, PhD (Chair), Washington University, T. David Elkin, PhD, University of Mississippi Medical Center, Kevin R. Krull, PhD, Baylor College of Medicine, Kimberly Rennie, PhD, Medical College of Wisconsin, and H. Gerry Taylor, PhD, Rainbow Babies and Children’s Hospital. Neuroradiology Committee—Robert C. McKinstry, MD, PhD (Chair), Washington University School of Medicine, William S. Ball, Jr., MD, University of Cincinnati, Michael A. Kraut, MD, PhD, Johns Hopkins University School of Medicine, and Marilyn Siegel, MD, Washington University School of Medicine. Neurology Committee—Michael J. Noetzel, MD, (Chair) Washington University School of Medicine, Rebecca N. Ichord, MD, Children’s Hospital of Philadelphia, E. Steve Roach, MD, Children’s Research Institute, The Ohio State University, Deborah Hirtz, MD, National Institute of Neurological Disorders and Stroke, and Michael Dowling, MD, PhD, University of Texas Southwestern Medical Center. The following investigators participated in the Silent Infarct Transfusion Trial: Michael R. DeBaun, MD, MPH, Washington University School of Medicine, St. Louis, MO.; Bruce Barton, PhD, Maryland Medical Research Institute, Inc., Baltimore, MD.; Fred Prior, PhD, Mallinckrodt Institute of Radiology at the Washington University School of Medicine, St. Louis, MO.; James F. Casella, MD, Harold Lehmann, MD and John J. Strouse, MD, Johns Hopkins University School of Medicine, Baltimore, MD; Scott T. Miller, MD, State University of New York-Downstate Medical Center/Kings County Hospital Center, Brooklyn, NY; Caterina Minniti, MD, Children’s Research Institute–Children’s National Medical Center, Washington, DC; Rupa Redding-Lallinger, MD, University of North Carolina at Chapel Hill, Chapel Hill, NC; Charles Daeschner, MD, East Carolina University, Greenville, NC; Anthony Villella, MD, Case Western Reserve University/Rainbow Babies and Children’s Hospital, Cleveland, OH; Mark A. Ranalli, MD, Columbus Children’s Hospital/Ohio State University College of Medicine and Public Health, Columbus OH; Karen Kalinyak, MD, University of Cincinnati, Cincinnati, OH; Mark Heiny, MD, Riley Hospital for Children/Indiana University, Indianapolis, IN; Ingrid A. Sarnaik, MD, Wayne State University, Detroit, MI; Alexis A. Thompson, MD, Northwestern University–Children’s Memorial Hospital, Chicago, IL; Julie Panepinto, MD, MSPH, Medical College of Wisconsin/Children’s Research Institute of the Children’s Hospital of Wisconsin, Milwaukee, WI; Gerald M. Woods, MD, University of Missouri-Kansas/Children’s Mercy Hospital, Kansas City, MO; Allison King, MD, MPH, Washington University School of Medicine/St. Louis Children’s Hospital, St. Louis, MO; Suzanne L. Saccente, MD, University of Arkansas/Arkansas Children’s Hospital Research Institute, Little Rock, AK.; Thomas Howard, MD, University of Alabama at Birmingham, Birmingham, AL; Rathi V. Iyer, MD, University of Mississippi Medical Center, Jackson, MS.; Gladstone Airewele, MD, MPH and Donald H. Mahoney, Jr., MD, Baylor College of Medicine, Houston, TX; Charles Scher, MD, Tulane University Health Sciences Center, New Orleans, LA; Charles T. Quinn, MD, University of Texas Southwestern Medical Center, Dallas, TX; Thomas Coates, MD, University of Southern California, Los Angeles, CA; Hernan Sabio, MD, Wake Forest School of Medicine, Winston-Salem, NC; Fenella Kirkham, MD, University College Hospital, Institute of Child Health, London, United Kingdom; Baba Inusa, MD, Guy’s and St. Thomas’ Foundation Trust, London, United Kingdom; Françoise Bernaudin, MD, Hôpital Intercommunal de Créteil, Créteil, France; Melanie A. Kirby, FRCP, The Hospital for Sick Children, Toronto, ON; and Deborah Hirtz, MD, National Institutes of Health (NINDS), Bethesda, MD.