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Silent Cerebral Infarct Transfusion (SIT) trial imaging core: application of novel imaging information technology for rapid and central review of MRI of the brain.

ABSTRACT: The Silent Cerebral Infarct Multicenter Transfusion (SIT) Trial is a multi-institutional intervention trial in which children with silent cerebral infarcts are randomized to receive either blood transfusion therapy or observation (standard care) for 36 months. The SIT Trial is scheduled to enroll approximately 1,880 children with sickle cell disease from 29 clinical sites in the United States, Canada, UK, and France. Each child undergoes a screening magnetic resonance imaging (MRI) of the brain to detect the presence of silent cerebral infarct-like lesions, a pre-randomization (baseline) MRI and exit MRI to determine if there are new or enlarged cerebral infarcts, using a designated, prospective imaging protocol. The objective of this manuscript is to describe the innovative method used to process and adjudicate imaging studies for an international trial with a primary endpoint that includes neuroimaging. Institution investigators at each site were provided with computer hardware and software for transmission of MRI images that allow them to strip the scans of all personal information and add unique study identifiers. Three neuroradiologists at separate academic centers review MRI studies and determine the presence or absence of silent cerebral infarct-like lesions. Their findings are subsequently placed on web-based case report forms and sent to the Statistical Coordinating Center. The average time from imaging center receipt of the MRI study to the radiology committee report back to the local site is less than two working days. This novel strategy was designed to maximize efficiency and minimize cost of a complex large multicenter trial that depends heavily on neuroimaging for entry criteria and assessment for the primary outcome measures. The technology, process, and expertise used in the SIT Trial can be adapted to virtually any clinical research trial with digital imaging requirements.

SUBMITTER: Vendt BA

PROVIDER: S-EPMC2801625 | biostudies-other | 2009 Jun

REPOSITORIES: biostudies-other

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Project description:In 2020, the American Society of Hematology published evidence-based guidelines for cerebrovascular disease in individuals with sickle cell anemia (SCA). Although the guidelines were based on National Institutes of Health-sponsored randomized controlled trials, no cost-effectiveness analysis was completed for children with SCA and silent cerebral infarcts. We conducted a cost-effectiveness analysis comparing regular blood transfusion vs standard care using SIT (Silent Cerebral Infarct Transfusion) Trial participants. This analysis included a modified societal perspective with direct costs (hospitalization, emergency department visit, transfusion, outpatient care, and iron chelation) and indirect costs (special education). Direct medical costs were estimated from hospitalizations from SIT hospitals and unlinked aggregated hospital and outpatient costs from SIT sites by using the Pediatric Health Information System. Indirect costs were estimated from published literature. Effectiveness was prevention of infarct recurrence. An incremental cost-effectiveness ratio using a 3-year time horizon (mean SIT Trial participant follow-up) compared transfusion vs standard care. A total of 196 participants received transfusions (n = 90) or standard care (n = 106), with a mean age of 10.0 years. Annual hospitalization costs were reduced by 54% for transfusions vs standard care ($4929 vs $10 802), but transfusion group outpatient costs added $22 454 to $137 022 per year. Special education cost savings were $2634 over 3 years for every infarct prevented. Transfusion therapy had an incremental cost-effectiveness ratio of $22 025 per infarct prevented. Children with preexisting silent cerebral infarcts receiving blood transfusions had lower hospitalization costs but higher outpatient costs, primarily associated with the oral iron chelator deferasirox. Regular blood transfusion therapy is cost-effective for infarct recurrence in children with SCA. This trial is registered at www.clinicaltrials.gov as #NCT00072761.

Project description:In stroke care, the extent of irreversible brain injury, termed infarct core, plays a key role in determining eligibility for acute treatments, such as intravenous thrombolysis and endovascular reperfusion therapies. Many of the pivotal randomized clinical trials testing those therapies used MRI Diffusion-Weighted Imaging (DWI) or CT Perfusion (CTP) to define infarct core. Unfortunately, these modalities are not available 24/7 outside of large stroke centers. As such, there is a need for accurate infarct core determination using faster and more widely available imaging modalities including Non-Contrast CT (NCCT) and CT Angiography (CTA). Prior studies have suggested that CTA provides improved predictions of infarct core relative to NCCT; however, this assertion has never been numerically quantified by automatic medical image computing pipelines using acquisition protocols not confounded by different scanner manufacturers, or other protocol settings such as exposure times, kilovoltage peak, or imprecision due to contrast bolus delays. In addition, single-phase CTA protocols are at present designed to optimize contrast opacification in the arterial phase. This approach works well to maximize the sensitivity to detect vessel occlusions, however, it may not be the ideal timing to enhance the ischemic infarct core signal (ICS). In this work, we propose an image analysis pipeline on CT-based images of 88 acute ischemic stroke (AIS) patients drawn from a single dynamic acquisition protocol acquired at the acute ischemic phase. We use the first scan at the time of the dynamic acquisition as a proxy for NCCT, and the rest of the scans as a proxy for CTA scans, with bolus imaged at different brain enhancement phases. Thus, we use the terms "NCCT" and "CTA" to refer to them. This pipeline enables us to answer the questions "Does the injection of bolus enhance the infarct core signal?" and "What is the ideal bolus timing to enhance the infarct core signal?" without being influenced by aforementioned factors such as scanner model, acquisition settings, contrast bolus delay, and human reader errors. We use reference MRI DWI images acquired after successful recanalization acting as our gold standard for infarct core. The ICS is quantified by calculating the difference in intensity distribution between the infarct core region and its symmetrical healthy counterpart on the contralateral hemisphere of the brain using a metric derived from information theory, the Kullback-Leibler divergence (KL divergence). We compare the ICS provided by NCCT and CTA and retrieve the optimal timing of CTA bolus to maximize the ICS. In our experiments, we numerically confirm that CTAs provide greater ICS compared to NCCT. Then, we find that, on average, the ideal CTA acquisition time to maximize the ICS is not the current target of standard CTA protocols, i.e., during the peak of arterial enhancement, but a few seconds afterward (median of 3 s; 95% CI [1.5, 3.0]). While there are other studies comparing the prediction potential of ischemic infarct core from NCCT and CTA images, to the best of our knowledge, this analysis is the first to perform a quantitative comparison of the ICS among CT based scans, with and without bolus injection, acquired using the same scanning sequence and a precise characterization of the bolus uptake, hence, reducing potential confounding factors.

Project description:Background and Purpose- The aim of this study is to determine the spatial and volumetric accuracy of infarct core estimates from relative cerebral blood flow (rCBF) by comparison with near-contemporaneous diffusion-weighted imaging (DWI), and evaluate whether it is sufficient for patient triage to reperfusion therapies. Methods- One hundred ninety-three patients enrolled in the DEFUSE 2 (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution) and SENSE 3 (Sensitivity Encoding) stroke studies were screened, and 119 who underwent acute magnetic resonance imaging with DWI and perfusion imaging within 24 hours of onset were included. Infarct core was estimated using reduced rCBF at 12 thresholds (<0.20-<0.44) and compared against DWI (apparent diffusion coefficient <620 10-6mm2/s). For each threshold, volumetric agreement between the rCBF and DWI core estimates was assessed using Bland-Altman, correlation, and linear regression analyses; spatial agreement was assessed using receiver operating characteristic analysis. Results- An rCBF threshold of 0.32 yielded the smallest mean absolute volume difference (14.7 mL), best linear regression fit (R2=0.84), and best spatial agreement (Youden index, 0.38; 95% CI, 0.34-0.41) between rCBF and DWI, with high correlation (r=0.91, P<0.05), a small mean volume difference (1.3 mL) and no fixed bias (P<0.05). At this threshold, 110 of 119 (92.4%) patients were correctly triaged when applying 70 mL as the volume limit for thrombectomy. Spatial agreement was better for prediction of large infarcts (>70 mL) than small infarcts (≤70 mL), with Youden indices of 0.53 (95% CI, 0.49-0.56) and 0.34 (95% CI, 0.30-0.37), respectively. Conclusions- Strong correlation and agreement with near-contemporaneous DWI indicate that infarct core estimates obtained using rCBF are sufficiently accurate for patient triage to reperfusion therapies. The identified optimal rCBF threshold of 0.32 closely approximates the threshold currently used in clinical practice.

Project description:OBJECTIVE: To develop a new method for the cardiac MR (CMR) quantification of peri-infarct ischaemia using fused perfusion and delayed-enhanced images and to evaluate this method using quantitative single photon emission CT (SPECT) imaging as a reference. METHODS: 40 patients presenting with peri-infarct ischaemia on a routine stress (99m)Tc-SPECT imaging were recruited. Within 8 days of the SPECT study, myocardial perfusion was evaluated using stress adenosine CMR. Using fused perfusion and delayed-enhanced images, peri-infarct ischaemia was quantified as the percentage of myocardium with stress-induced perfusion defect that was adjacent to and larger than a scar. This parameter was compared with both the percent myocardium ischaemia (SD%) and the ischaemic total perfusion deficit (TPD). The diagnostic performance of CMR in detection of significant coronary artery stenosis (of ≥70%) was also determined. RESULTS: On SPECT imaging, in addition to peri-infarct ischaemia, reversible perfusion abnormalities were detected in a remote zone in seven patients. In the 33 patients presenting with only peri-infarct ischaemia, the agreement between CMR peri-infarct ischaemia and both SD% and ischaemic TPD was excellent [intraclass coefficient of correlation (ICC) = 0.969 and ICC = 0.877, respectively]. CMR-defined peri-infarct ischaemia for the detection of a significant coronary artery stenosis showed an areas under receiver-operating characteristic curve of 0.856 (95% confidence interval, 0.680-0.939). The best cut-off value was 8.1% and allowed a 72% sensitivity, 96% specificity, 60% negative predictive value and 97% positive predictive value. CONCLUSION: This proof-of-concept study shows that CMR imaging has the potential as a test for quantification of peri-infarct ischaemia. ADVANCES IN KNOWLEDGE: This study demonstrates the proof of concept of a commonly known intuitive idea, that is, evaluating the peri-infarct ischaemic burden by subtracting delayed enhancement from first-pass perfusion imaging on CMR.

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Silent Cerebral Infarct Transfusion (SIT) trial imaging core: application of novel imaging information technology for rapid and central review of MRI of the brain.

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