David M. DeLong

Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach.

Methods of evaluating and comparing the performance of diagnostic tests are of increasing importance as new tests are developed and marketed. When a test is based on an observed variable that lies on a continuous or graded scale, an assessment of the overall value of the test can be made through the use of a receiver operating characteristic (ROC) curve. The curve is constructed by varying the cutpoint used to determine which values of the observed variable will be considered abnormal and then plotting the resulting sensitivities against the corresponding false positive rates. When two or more empirical curves are constructed based on tests performed on the same individuals, statistical analysis on differences between curves must take into account the correlated nature of the data. This paper presents a nonparametric approach to the analysis of areas under correlated ROC curves, by using the theory on generalized U-statistics to generate an estimated covariance matrix.

Effect of a Novel Free Radical Scavenger, Edaravone (MCI-186), on Acute Brain Infarction

Edaravone, a novel free radical scavenger, demonstrates neuroprotective effects by inhibiting vascular endothelial cell injury and ameliorating neuronal damage in ischemic brain models. The present study was undertaken to verify its therapeutic efficacy following acute ischemic stroke. We performed a multicenter, randomized, placebo-controlled, double-blind study on acute ischemic stroke patients commencing within 72 h of onset. Edaravone was infused at a dose of 30 mg, twice a day, for 14 days. At discharge within 3 months or at 3 months after onset, the functional outcome was evaluated using the modified Rankin Scale. Two hundred and fifty-two patients were initially enrolled. Of these, 125 were allocated to the edaravone group and 125 to the placebo group for analysis. Two patients were excluded because of subarachnoid hemorrhage and disseminated intravascular coagulation. A significant improvement in functional outcome was observed in the edaravone group as evaluated by the modified Rankin Scale (p = 0.0382). Edaravone represents a neuroprotective agent which is potentially useful for treating acute ischemic stroke, since it can exert significant effects on functional outcome as compared with placebo.

APOE genotype as a risk factor for ischemic cerebrovascular disease: A meta-analysis

Objective: To determine whether a specific apolipoprotein E (APOE) polymorphism is a risk factor for ischemic cerebrovascular disease (CVD; stroke or TIA). Background: The APOE ε4 allele is overrepresented in AD, atherosclerosis, and ischemic heart disease. In addition, ε4 carriers have higher plasma cholesterol levels than non-ε4 carriers. Methods: Using Medline (OVID and PubMed), a search was performed for all studies that examined APOE in ischemic CVD. The authors identified nine case–control studies that were suitable for analysis. Results: There were 926 patients with ischemic stroke or TIAs and 890 age- and sex-matched control subjects. Overall analysis revealed a significantly higher APOE-ε4 allelic frequency in affected patients compared with control subjects (0.14 versus 0.09; odds ratio, 1.68; 95% CI, 1.36 to 2.09; p < 0.001 ). There was a significant excess of the ε3 allele (0.85 versus 0.80) but not the ε2 allele (0.06 versus 0.06) in the control subjects compared with the ischemic CVD patients. Seven studies had data on APOE genotypes. Carriers of ε4 were more frequent among ischemic CVD patients than control subjects (27% versus 18%; odds ratio, 1.73; 95% CI, 1.34 to 2.23; p < 0.001). Conclusions: The APOE-ε4 allele and carriers of ε4 are more frequent among patients with ischemic CVD compared with control subjects. The ε2 allele does not appear to be protective for ischemic CVD. These findings imply a role for the APOE genotype in the pathogenesis of some cases of ischemic CVD.

Making the diagnosis of acute appendicitis: Do more preoperative CT scans mean fewer negative appendectomies? A 10-year study

PURPOSE To determine the frequency of preoperative computed tomography (CT) in the evaluation of patients suspected of having appendicitis at one institution during the past 10 years and to determine whether changes in CT utilization were associated with changes in the negative appendectomy rate. MATERIALS AND METHODS Institutional review board approval was obtained, and a waiver of informed consent was granted for this HIPAA-compliant study. A surgical database search yielded medical record numbers of 925 patients (526 [ 56.9%] men and 399 [43.1%] women; mean age, 38 years (range, 18-95 years]) who underwent urgent appendectomy between January 1998 and September 2007. Patients who were younger than 18 years of age at the time of surgery were excluded. CT, pathology, and surgery reports were reviewed. By using logistic regression, changes in the proportion of patients undergoing CT and in the proportion of patients undergoing each year appendectomy in which the appendix was healthy were evaluated. Subgroup analyses based on patient age (<or= 45 years or > 45 years) and sex also were performed. RESULTS Prior to urgent appendectomy, 18.5% of patients underwent preoperative CT in 1998 compared with 93.2% of patients in 2007. The negative appendectomy rate for women 45 years of age and younger decreased from 42.9% in 1998% to 7.1% in 2007. However, the timing of the decline in negative appendectomy rates for women 45 years and younger could not be proved to be associated with the increase in CT use. There was no significant trend toward a lower negative appendectomy rate for men regardless of age or for women older than 45 years of age with increased use of preoperative CT. The shift from single-detector CT to multidetector CT and the use of decreasing section thickness also correlated with a reduction in false-positive diagnoses. CONCLUSION Rising utilization of preoperative CT and advances in technology coincided with a decrease in the negative appendectomy rate for women 45 years and younger but not in men of any age or women older than 45 years.

Digital tomosynthesis of the chest for lung nodule detection: Interim sensitivity results from an ongoing NIH‐sponsored trial

The authors report interim clinical results from an ongoing NIH-sponsored trial to evaluate digital chest tomosynthesis for improving detectability of small lung nodules. Twenty-one patients undergoing computed tomography (CT) to follow up lung nodules were consented and enrolled to receive an additional digital PA chest radiograph and digital tomosynthesis exam. Tomosynthesis was performed with a commercial CsI/a-Si flat-panel detector and a custom-built tube mover. Seventy-one images were acquired in 11 s, reconstructed with the matrix inversion tomosynthesis algorithm at 5-mm plane spacing, and then averaged (seven planes) to reduce noise and low-contrast artifacts. Total exposure for tomosynthesis imaging was equivalent to that of 11 digital PA radiographs (comparable to a typical screen-film lateral radiograph or two digital lateral radiographs). CT scans (1.25-mm section thickness) were reviewed to confirm presence and location of nodules. Three chest radiologists independently reviewed tomosynthesis images and PA chest radiographs to confirm visualization of nodules identified by CT. Nodules were scored as: definitely visible, uncertain, or not visible. 175 nodules (diameter range 3.5-25.5 mm) were seen by CT and grouped according to size: < 5, 5-10, and > 10 mm. When considering as true positives only nodules that were scored definitely visible, sensitivities for all nodules by tomosynthesis and PA radiography were 70% (+/- 5%) and 22% (+/- 4%), respectively, (p < 0.0001). Digital tomosynthesis showed significantly improved sensitivity of detection of known small lung nodules in all three size groups, when compared to PA chest radiography.

Hippocampal MRI signal hyperintensity after febrile status epilepticus is predictive of subsequent mesial temporal sclerosis.

OBJECTIVE The objective of our study was to test the hypothesis that the finding of hyperintense hippocampal signal intensity on T2-weighted MR images soon after febrile status epilepticus is associated with subsequent hippocampal volume loss and persistent abnormal signal intensity on T2-weighted images (i.e., mesial temporal sclerosis). SUBJECTS AND METHODS Eleven children (mean age, 25 months) underwent initial MRI that included coronal temporal lobe imaging within 72 hours of febrile status epilepticus and follow-up imaging from 3 to 23 months later (mean, 9 months). A neuroradiologist blinded to clinical history graded initial and follow-up hippocampal signal intensity on a scale from 0 (normal) to 4 (markedly increased). Two blinded observers measured hippocampal volumes on initial and follow-up MR studies using commercially available software and volumes from 30 healthy children (mean age, 6.3 years). Initial signal intensity and hippocampal volume changes were compared using Kendall tau correlation coefficients. RESULTS On initial imaging, hyperintense signal intensity ranging from 1 (minimally increased) to 4 (markedly increased) was seen in seven children. Four children had at least one hippocampus with moderate or marked signal abnormality, three children had a hippocampus with mild or minimal abnormality, and four children had normal signal intensity. The Kendall tau correlation coefficient between signal intensity increase and volume change was -0.68 (p < 0.01). Five children (two with temporal lobe epilepsy and two with complex partial seizures) had hippocampal volume loss and increased signal intensity on follow-up imaging, meeting the criteria for mesial temporal sclerosis. CONCLUSION MRI findings of a markedly hyperintense hippocampus in children with febrile status epilepticus was highly associated with subsequent mesial temporal sclerosis.

Diffusion Tensor Imaging Assessment of Brain White Matter Maturation During the First Postnatal Year

OBJECTIVE The purpose of this study was to use diffusion-weighted and diffusion tensor imaging to investigate the status of cerebral white matter (WM) at term gestation and the rate of WM maturation throughout the first year of life in healthy infants. MATERIALS AND METHODS Fifty-three children (35 boys) ranging in age from 1.5 weeks premature to 51.5 weeks (mean age, 22.9 weeks) underwent conventional MRI, diffusion imaging in three directions (b = 1,000 s/mm2), and diffusion tensor imaging with gradient encoding in six directions, all on a 1.5-T MRI system. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in three deep WM structures (posterior limb of internal capsule, genu, and splenium of corpus callosum) and two peripheral WM regions (associational WM underlying prefrontal and posterior parietal cortex) with a standard region of interest (44 +/- 4 cm2). ADC and FA were expressed as a percentage of corresponding values measured in a group of healthy young adults. Mean ADC and FA values for deep and peripheral WM were plotted against gestational age normalized to term. The data were fit best with a broken-line linear regression model with a breakpoint at 100 days. ADC and FA values at term were estimated according to the intercept of the initial linear period (before day 100) with day 0. The slope of the linear fits was used to determine the rate of WM maturation in both the early and the late (after day 100) periods. Multivariate analysis of variance tests were used to compare deep and peripheral WM structures at term and at representative early and late ages (days 30 and 200) and to compare rates of ADC and FA maturation in early and late periods within the first year. RESULTS At term, peripheral WM was less mature than deep WM according to results of extrapolation of ADC and FA values in the first 100 days of life to day 0 (p < 0.01). Mean ADC and FA value (percentage of mean adult value) for peripheral WM were 1.32 x 10(-3) mm2/s (163%) and 0.16 (32%), respectively, and 1.09 x 10(-3) mm2/s (143%) and 0.36 (54%), respectively, for deep WM. On day 30 and day 200, estimated mean ADC and FA continued to show greater diffusion (higher ADC) and less anisotropy (lower FA value) in peripheral WM (p <0.01). During the first year of postnatal life, both ADC and FA matured at higher rates before postnatal day 100 compared with a later time. Differences were observed in rates of maturation in the first 100 days when rates of decrease in ADC and increase in FA were compared between peripheral WM and deep WM; however, the maturational trends differed whether ADC or FA was examined. The early rate of ADC decrease (maturation) was twice as great for peripheral WM than for deep WM (p < 0.01) unexpectedly, but the opposite pattern was observed for FA. The early rate of FA increase (maturation) was approximately one half as great for peripheral WM as for deep WM (p = 0.01). Throughout the rest of the first year, no differences were observed in the rates of change in either index between peripheral WM and deep WM. CONCLUSION At term, both ADC and FA differ significantly in peripheral WM and deep WM, deep WM structures being more mature. Both deep WM and peripheral WM mature more rapidly during approximately the first 3 months in comparison with the rest of the first year. Unexpected differences in early (first 100 days) rates of maturation assessed with diffusion-weighted (ADC) and diffusion tensor (FA) imaging suggest that these two techniques may be sensitive to different aspects of WM maturation in the early perinatal period.

Effect of patient size on radiation dose for abdominal MDCT with automatic tube current modulation: phantom study

OBJECTIVE The purpose of this study was to evaluate in a phantom study the effect of patient size on radiation dose for abdominal MDCT with automatic tube current modulation. MATERIALS AND METHODS One or two 4-cm-thick circumferential layers of fat-equivalent material were added to the abdomen of an anthropomorphic phantom to simulate patients of three sizes: small (cross-sectional dimensions, 18 x 22 cm), average size (26 x 30 cm), and oversize (34 x 38 cm). Imaging was performed with a 64-MDCT scanner with combined z-axis and xy-axis tube current modulation according to two protocols: protocol A had a noise index of 12.5 H, and protocol B, 15.0 H. Radiation doses to three abdominal organs and the skin were assessed. Image noise also was measured. RESULTS Despite increasing patient size, the image noise measured was similar for protocol A (range, 11.7-12.2 H) and protocol B (range, 13.9-14.8 H) (p > 0.05). With the two protocols, in comparison with the dose of the small patient, the abdominal organ doses of the average-sized patient and the oversized patient increased 161.5-190.6%and 426.9-528.1%, respectively (p < 0.001). The skin dose increased as much as 268.6% for the average-sized patient and 816.3% for the oversized patient compared with the small patient (p < 0.001). CONCLUSION Oversized patients undergoing abdominal MDCT with tube current modulation receive significantly higher doses than do small patients. The noise index needs to be adjusted to the body habitus to ensure dose efficiency.

Estimation of myocardial blood flow for longitudinal studies with 13N-labeled ammonia and positron emission tomography

BackgroundAlthough several modeling strategies have been developed and validated for quantification of myocardial blood flow (MBF) from 13N-labeled ammonia positron emission tomographic data, a comparison of noise characteristics of the various techniques in serial studies is lacking.Methods and ResultsDynamic 13N-labeled ammonia positron emission tomographic imaging was performed at baseline and after pharmacologic stress in (1) single studies of four dogs with concomitant measurement of microsphere blood flow and (2) initial and follow-up studies of eight normal volunteers. Data were obtained from short-axis images for the blood pool and myocardial regions corresponding to the three arterial vascular territories. Indexes of MBF were obtained by four distinct techniques: (1) University of California, Los Angeles, twocompartment model, (2) Michigan two-compartment model, and (3) a one-compartment model with variable blood volume term. Coronary flow reserve (CFR) was measured as the ratio of stress/rest MBF. The estimated standard deviation of the measurement error for the relative change between studies of rest and stress MBF and CFR was determined for each technique. Estimates of MBF from all techniques showed good correlation with microsphere blood flow (r=0.95 to 0.96) in canine myocardium. In human studies, similar mean estimates of MBF were found with all techniques. Techniques 1 and 3 showed the smallest interstudy variability in MBF and CFR. The estimated standard deviations for these techniques were approximately 20%, 30%, and 27% for rest MBF, stress MBF, and CFR, respectively.ConclusionNoninvasive quantification of MBF and CFR from dynamic 13N-labeled ammonia positron emission tomography is most reproducible with technique 1 or 3. The ability to account for differences in myocardial partial volume gives preference to technique 3. However, substantial interstudy variability in regional MBF remains, suggesting the importance of procedural factors or real temporal fluctuations in MBF.

Accuracy of Abdominal Radiography in Acute Small-Bowel Obstruction: Does Reviewer Experience Matter?

OBJECTIVE The purposes of this study were to determine the accuracy of abdominal radiography in the detection of acute small-bowel obstruction (SBO), to assess the role of reviewer experience, and to evaluate individual radiographic signs of SBO. MATERIALS AND METHODS A retrospective study was performed in which the subjects were 90 patients with suspected SBO who underwent CT and abdominal radiography within 48 hours of each other. The patients were enrolled from June 1, 2003, to February 2004. Twenty-nine of the patients had proven SBO. Hard-copy radiographs were reviewed by three groups of radiologists: senior staff, junior staff, and second-year radiology residents. Each reviewer evaluated the quality of the radiographs, patient position for acquisition of the radiographs, and whether SBO was present. The reviewers rated their confidence on a five-point scale and recorded the presence or absence of specific radiographic signs of SBO. Chi-square tests were used to compare the three groups. A statistically significant finding was considered p < 0.05. Receiver operating characteristic (ROC) curves were fit with a 10-point confidence scale. RESULTS The sensitivity for SBO among the six reviewers ranged from 59% to 93%. The senior staff members were significantly more accurate. The mean sensitivity, specificity, and accuracy for all six reviewers were 82%, 83%, and 83%, respectively. Three radiographic signs were highly significant (p < 0.001): two or more air-fluid levels, air-fluid levels wider than 2.5 cm, and air-fluid levels differing more than 5 mm from one another in the same loop of small bowel. ROC analysis showed that senior staff is significantly more accurate than the other groups in the detection of acute SBO. CONCLUSION Our results confirmed that abdominal radiographs are accurate in the detection of acute SBO, that more-experienced radiologists are more accurate than less-experienced reviewers in the evaluation of abdominal radiographs, and that three types of air-fluid levels are highly predictive of the presence of SBO.