Investigating the predictive value of whole-brain structural MR scans in autism: A pattern classification approach

Autistic spectrum disorder (ASD) is accompanied by subtle and spatially distributed differences in brain anatomy that are difficult to detect using conventional mass-univariate methods (e.g., VBM). These require correction for multiple comparisons and hence need relatively large samples to attain sufficient statistical power. Reports of neuroanatomical differences from relatively small studies are thus highly variable. Also, VBM does not provide predictive value, limiting its diagnostic value.Here, we examined neuroanatomical networks implicated in ASD using a whole-brain classification approach employing a support vector machine (SVM) and investigated the predictive value of structural MRI scans in adults with ASD. Subsequently, results were compared between SVM and VBM. We included 44 male adults; 22 diagnosed with ASD using “gold-standard” research interviews and 22 healthy matched controls.SVM identified spatially distributed networks discriminating between ASD and controls. These included the limbic, frontal-striatal, fronto-temporal, fronto-parietal and cerebellar systems. SVM applied to gray matter scans correctly classified ASD individuals at a specificity of 86.0% and a sensitivity of 88.0%. Cases (68.0%) were correctly classified using white matter anatomy. The distance from the separating hyperplane (i.e., the test margin) was significantly related to current symptom severity. In contrast, VBM revealed few significant between-group differences at conventional levels of statistical stringency.We therefore suggest that SVM can detect subtle and spatially distributed differences in brain networks between adults with ASD and controls. Also, these differences provide significant predictive power for group membership, which is related to symptom severity.     

Coronary patency, infarct size and left ventricular function after thrombolytic therapy for acute myocardial infarction: results from the tissue plasminogen activator: Toronto (TPAT) placebo-controlled trial. TPAT Study Group

Infarct size, left ventricular function and infarct-related coronary artery patency were examined in 108 patients who took part in a previously reported placebo-controlled trial of recombinant tissue-type plasminogen activator (rt-PA) in acute myocardial infarction. Coronary angiography was performed 17 +/- 0.8 h after initiation of treatment in 47 patients (group A) or at 10 days in 61 patients (group B). Both groups underwent radionuclide ventriculography 3.8 +/- 0.8 h and again on day 9 after treatment and quantitative thallium scintigraphy on day 8. In group A, the infarct-related artery was patent in 53%; these patients had a smaller global (15.1 +/- 2.5% vs. 25.7 +/- 4.7%, p = 0.029) and regional (14.7 +/- 2.5% vs. 24.1 +/- 4.7%, p = 0.044) fixed thallium defect than did those with an occluded artery. Infarct regional ejection fraction improved by 10.1 +/- 2.1% between early and late studies when the infarct-related artery was patent and by 4.8 +/- 1.4% if it was occluded (p = 0.048); changes in global and noninfarct regional ejection fraction were similar irrespective of perfusion status. Infarct regional ejection fraction and fixed thallium defect were inversely related only when the infarct-related artery was occluded (r = -0.83, p less than 0.0001). In group B, 10 day patency of the infarct-related artery was 67%; there was no difference in patency by treatment assignment or in left ventricular function or infarct size between patients with and without infarct-related artery patency. There was no evidence of an effect of rt-PA therapy beyond that expressed through coronary patency alone in either group A or group B.     

A soluble form of Fc gamma RIII is present in human serum and other body fluids and is elevated at sites of inflammation.

We have developed a highly sensitive and specific sandwich enzyme-linked immunosorbent assay (ELISA) to measure the concentration of Fc gamma RIII in serum and other body fluids. This ELISA is based on the use of monoclonal antibody (MoAb) (3G8) to Fc gamma RIII and a rabbit antiserum against Fc gamma RIII. The lower limit of detection of this ELISA was 1.5 nmol/L. The concentration of soluble Fc gamma RIII in normal serum ranged from 7.3 to 75.9 nmol/L. Soluble Fc gamma RIII was also present in other normal biologic fluids such as saliva, urine, and seminal fluid, but at much lower concentrations than that found in serum. Rabbit anti-Fc gamma RIII immunoblotted polypeptides immunoprecipitated with MoAb 3G8. Fc gamma RIII immunoprecipitated from a neutrophil lysate migrated from 40 to 76 Kd, whereas Fc gamma RIII immunoprecipitated from serum from the same donor migrated from 40 to 66 Kd. The soluble form of Fc gamma RIII apparently was bound to serum IgG, because immunoprecipitation of soluble Fc gamma RIII by MoAb 3G8 coprecipitated polypeptides that were identified by goat antihuman IgG. Incubation of neutrophils in vitro at 4 degrees C and 37 degrees C showed that Fc gamma RIII was released after 30 minutes of incubation at 37 degrees C. To determine whether there was a correlation between the concentration of soluble Fc gamma RIII in biologic fluids and inflammatory diseases, we measured the concentration of Fc gamma RIII in the bronchoalveolar lavage fluid from patients with adult respiratory distress syndrome (ARDS) and in the synovial fluid from patients with various forms of arthritis. In ARDS, we found concentrations of soluble Fc gamma RIII that were five to seven times higher than that found in the bronchoalveolar lavage fluids from healthy adults. The concentration of soluble Fc gamma RIII in the synovial fluid from patients with rheumatoid arthritis ranged from 10 nmol/L to 28 mumol/L. These results suggest that activated neutrophils, such as those at sites of inflammation, may release Fc gamma RIII.     

Identifying Stage B colorectal cancer patients at high risk of tumor recurrence and death

PURPOSE: This study was designed to determine clinical and pathologic variables associated with poor outcome following resection of Stage B colorectal cancer. METHODS: This was a retrospective study of 117 patients with Stage B cancer who underwent curative surgery and survived the postoperative period. Fourteen clinical and pathologic features were studied. Clinical data were extracted from a prospective colorectal cancer database, and histologic slides were retreived and examined by a pathologist blinded as to clinical details and outcome. RESULTS: After a median follow-up period of 8.2 years, bowel obstruction was significantly related to a poor prognosis (log-rank test; P=0.03). Extensive necrosis (P =0.01) and perineural invasion (P = 0.03) were also associated with decreased survival. Vascular invasion was associated with poor long-term outcome in the subgroup of patients with rectal (P =0.07) but not colonic (P =0.57) cancer. Multivariate regression analysis identified both tumor necrosis (P =0.01) and perineural invasion (P =0.03) as independently related to outcome. CONCLUSION: Further study of prognostic indicators might result in an algorithm to distinguish Stage B cases at high risk of tumor recurrence and death. Such patients could be included in future trials of adjuvant therapies.Presented in part at the meeting of the American Gastroenterological Association, Boston, Massachusetts, May 16 to 19, 1993. Published in abstract form in Gastroenterology 1993;104:A432.     

Evidence that thrombocytopenia observed in humans treated with orally bioavailable glycoprotein IIb/IIIa antagonists is immune mediated

Glycoprotein (GP) IIb/IIIa antagonists are effective therapeutic agents, but elicit thrombocytopenia with a frequency that approaches 2%. Here, we provide evidence that thrombocytopenia in humans treated with the GP IIb/IIIa antagonist roxifiban is immune mediated. Two patients underwent conversion to a highly positive drug-dependent antibody (DDAB) status temporally associated with thrombocytopenia. Despite the continued presence of DDABs, the fall in platelet count was reversed by discontinuation of drug treatment, pointing to the exquisite drug dependency of the immune response. DDABs appear to bind to neoepitopes in GP IIb/IIIa elicited on antagonist binding. This information was used to develop an enzyme-linked immunosorbent assay (ELISA) for DDAB using solid-phase GP IIb/IIIa. A high level of specificity is indicated by the observation that DDAB binding is dependent on the chemical structure of the GP IIb/IIIa antagonist and that only 2% to 5% of human blood donors and 5% of chimpanzees present with pre-existing DDABs. Furthermore, none of 108 nonthrombocytopenic patients from the phase II roxifiban study showed an increase in antibody titer. Absorption of thrombocytopenia plasma with platelets reduced the DDAB ELISA signal, indicating that the test detects physiologically relevant antibodies. Screening patients for pre-existing or increasing DDAB titer during treatment with GP IIb/IIIa antagonists may reduce the incidence of drug-induced thrombocytopenia.     

Rapid Detection of Rare Deleterious Variants by Next Generation Sequencing with Optional Microarray SNP Genotype Data

Autozygosity mapping is a powerful technique for the identification of rare, autosomal recessive, disease‐causing genes. The ease with which this category of disease gene can be identified has greatly increased through the availability of genome‐wide SNP genotyping microarrays and subsequently of exome sequencing. Although these methods have simplified the generation of experimental data, its analysis, particularly when disparate data types must be integrated, remains time consuming. Moreover, the huge volume of sequence variant data generated from next generation sequencing experiments opens up the possibility of using these data instead of microarray genotype data to identify disease loci. To allow these two types of data to be used in an integrated fashion, we have developed AgileVCFMapper, a program that performs both the mapping of disease loci by SNP genotyping and the analysis of potentially deleterious variants using exome sequence variant data, in a single step. This method does not require microarray SNP genotype data, although analysis with a combination of microarray and exome genotype data enables more precise delineation of disease loci, due to superior marker density and distribution.     

A concise guide to clinical reasoning

What constitutes clinical reasoning is a disputed subject regarding the processes underlying accurate diagnosis, the importance of patient‐specific versus population‐based data, and the relation between virtue and expertise in clinical practice. In this paper, I present a model of clinical reasoning that identifies and integrates the processes of diagnosis, prognosis, and therapeutic decision making. The model is based on the generalized empirical method of Bernard Lonergan, which approaches inquiry with equal attention to the subject who investigates and the object under investigation. After identifying the structured operations of knowing and doing and relating these to a self‐correcting cycle of learning, I correlate levels of inquiry regarding what‐is‐going‐on and what‐to‐do to the practical and theoretical elements of clinical reasoning. I conclude that this model provides a methodical way to study questions regarding the operations of clinical reasoning as well as what constitute significant clinical data, clinical expertise, and virtuous health care practice.     

System Strategies for Colorectal Cancer Screening at Federally Qualified Health Centers

Objectives. We assessed the protocols and system processes for colorectal cancer (CRC) screening at federally qualified health centers (FQHCs) in 4 midwestern states.Methods. We identified 49 FQHCs in 4 states. In January 2013, we mailed their medical directors a 49-item questionnaire about policies on CRC screening, use of electronic medical records, types of CRC screening recommended, clinic tracking systems, referrals for colonoscopy, and barriers to providing CRC.Results. Forty-four questionnaires (90%) were returned. Thirty-three of the respondents (75%) estimated the proportion of their patients up-to-date with CRC screening, with a mean of 35%. One major barrier to screening was inability to provide colonoscopy for patients with a positive fecal occult blood test (59%). The correlation of system strategies and estimated percentage of patients up-to-date with CRC screening was 0.43 (P = .01).Conclusions. CRC system strategies were associated with higher CRC screening rates. Implementing system strategies for CRC screening takes time and effort and is important to maintain, to help prevent, or to cure many cases of CRC, the second leading cause of cancer in the United States.Federally qualified health centers (FQHCs) attempt to provide comprehensive, quality primary health care services to medically underserved communities and vulnerable populations. Approximately 1198 centers receive operating grants from the Public Health Service Act and thus qualify for reimbursement from Medicare and Medicaid.1 FQHCs served 21 million patients in 2012, of whom 36% were uninsured and 92% were living below the 200% poverty level.1 One of the services provided by FQHCs is colorectal cancer (CRC) screening through stool testing for occult blood.2 This service is covered under the Medicare FQHC benefit for persons aged 65 years and older and for those who qualify for the Medicaid program.3CRC is the second leading cause of cancer deaths in the United States.4 Only 63% of US adults report being up-to-date with CRC screening.5 CRC is a disease that is largely preventable; colonoscopy, through detection of early tumors and removal of precancerous polyps, could prevent 65% of CRC cases.6,7 Several national organizations have guidelines for CRC screening.8,9 National guidelines promote any of several tests for CRC screening: tests that pick up occult bleeding and endoscopic tests that visualize all or part of the colon.8–10Clinical tests to directly visualize colorectal cancer and precancerous polyps are colonoscopy, flexible sigmoidoscopy, double-contrast barium enema, and computed tomographic colonography (virtual colonoscopy). Fecal occult blood tests (FOBTs), which detect blood in the stool that is not visible and that indicates possible cancer, are the guaiac-based test and the fecal immunochemical test (FIT). FOBTs are recommended annually, and colonoscopy is recommended every 10 years, if no polyps are found.8–10 FOBTs are much less expensive than colonoscopy and are often preferred by patients. In many safety net settings, FOBTs are the initial option for patients, because of the prohibitive cost and limited availability of colonoscopy.11,12Through an infrastructure grant to enhance community-based cancer control in Iowa, we visited 4 FQHCs in Iowa and learned that FOBTs were available for use, but were for the most part not given to patients to avoid having to arrange and pay for a follow-up colonoscopy if FOBT results were positive. One FQHC director explained that the annual budget included a fund for extra tests that might be needed for any medical reason, and once these funds were exhausted, no more funding was available in that year. Thus, CRC screening was not a top priority, because of many other competing health care needs.To enhance CRC screening, system strategies are appropriate. A system strategy is a group of interrelated items that are part of a plan of action to accomplish a specific goal, such as improving CRC screening. Many different system strategies have been identified for improving CRC screening, such as physician recommendation,13,14 mailed patient reminders,15–17 and electronic medical record (EMR) physician reminders.18,19Patients at greatest risk for not receiving CRC screening are racial and ethnic minorities, Asians and Hispanics, and individuals who lack a usual source of health care or health insurance.20 Underuse of CRC screening is frequently associated with socioeconomic disadvantage21 and is associated with higher late-stage CRC rates.22 Because many of our nation’s most disadvantaged individuals make use of FQHCs, we assessed the protocols and system processes in place for CRC screening at FQHCs in 4 midwestern states and estimated rates of CRC screening in these FQHCs.