PubChem3D: Shape compatibility filtering using molecular shape quadrupoles

Differential Methylation Profile of Ovarian Cancer in Tissues and Plasma

Integration of computational methods in the early stages of drug discovery has been one of the key trends in the pharmaceutical industry. Starting with high quality drug candidates should ultimately minimize clinical attrition rates and give rise to higher success rates. In this paper, we present a novel approach for indexing oral druglikeness of compounds. With the Iterative Stochastic Elimination (ISE) Algorithm, we distinguish between orally available drugs and nondrugs by generating sets of optimized descriptors' ranges, each set constituting a "filter". We delineate in this paper how to produce an ensemble of best k-descriptor sets out of the huge number of possibilities, and how to construct a "filter bank" that retains diverse filters by clustering. Finally, we define the "orally bioavailable drug-like" character of individual molecules by combining the filters into an "Orally Bioavailable Druglike Index" (OB-DLI) which may be used to prioritize molecules in databases and discuss its uses in several potential applications. The predictive power with sets of 4-6 descriptors is high (i.e., one filter of 5 descriptors retrieved 81% true positives and >77% true negatives). Thus, OB-DLI has advantages over binary decisions (that use only one filter) not only in raising discriminative power but also in ranking drug candidates according to their chance to be successful oral drugs. We demonstrate the ability of our approach to discover molecular entities with the required property, orally bioavailable drug likeness, that are structurally dissimilar to those of the training set. Comparison of this ISE application to some of the current main methods for classification reveals that our approach has >13% improvement in the Matthews Correlation Coefficient, which measures the success of identifying true and false positives and negatives.

Extra-axillary nodal metastases in breast cancer: comparison of ultrasound, MRI, PET/CT, and CT

Inadvertent injury of the recurrent laryngeal nerve can occur during radiofrequency ablation (RFA) of thyroid nodules. Methods to avoid permanent injury have not been described. Laryngeal ultrasonography (LUSG) can assess the function of vocal cords (VCs) in real time. The present study aimed to evaluate the feasibility and accuracy of LUSG in assessing real-time VC function during RFA of benign thyroid nodules. Consecutive patients undergoing RFA for benign thyroid nodules under local anesthesia were included. Spontaneous VC movements were checked with intra-operative LUSG (iLUSG) following each transverse ablation plane. In case of reduced VC movement, the ablation was stopped immediately. Post-ablation VC function was rechecked by LUSG on day-0 and flexible laryngoscopy (FL) on day-7. A concordance with day-0 LUSG or day-7 FL was a "true positive" or "true negative" depending on the presence or absence of VC palsy (VCP). Accuracy was calculated as the sum of all true positives and negatives divided by total nerves-at-risk. Of 65 eligible patients, 56 (86.2%) were females. Twelve (18.5%) patients had bilateral lobe RFA, while 53 (81.5%) had unilateral RFA. The total number of nerves-at-risk was 77. Three unilateral VCPs (3.9%) were initially detected on iLUSG and confirmed by day-0 LUSG. All recovered fully within one week. The overall accuracy of iLUSG was 100%. iLUSG is a highly accurate method that permits real-time feedback on the function of the VCs during RFA procedure. Real-time detection of VCP may prevent permanent injury. Methodological routine use of iLUSG is recommended during thyroid RFA.

Receiver operator characteristic (ROC) analysis is an emerging automated target recognition system performance assessment tool. The ROC metric, area under the curve (AUC), is a universally accepted measure of classifying accuracy. In the presented approach, the detection algorithm output, i.e., a response plane (RP), must consist of grayscale values wherein a maximum value (e.g. 255) corresponds to highest probability of target locations. AUC computation involves the comparison of the RP and the ground truth to classify RP pixels as true positives (TP), true negatives (TN), false positives (FP), or false negatives (FN). Ideally, the background and all objects other than targets are TN. Historically, evaluation methods have excluded the background, and only a few spoof objects likely to be considered as a hit by detection algorithms were a priori demarcated as TN. This can potentially exaggerate the algorithm's performance. Here, a new ROC approach has been developed that divides the entire image into mutually exclusive target (TP) and background (TN) grid squares with adjustable size. Based on the overlap of the thresholded RP with the TP and TN grids, the FN and FP fractions are computed. Variation of the grid square size can bias the ROC results by artificially altering specificity, so an assessment of relative performance under a constant grid square size is adopted in our approach. A pilot study was performed to assess the method's ability to capture RP changes under three different detection algorithm parameter settings on ten images with different backgrounds and target orientations. An ANOVA-based comparison of the AUCs for the three settings showed a significant difference (p<0.001) at 95% confidence interval.

Background : In resent years, crime rate has been increased. The aim of this study was to evaluate the computer assisted hand tracing overlay method for bite mark analysis. Methods: Impressions of both, maxillary as well as mandibular arches of 50 consenting volunteers were taken and dentition casts were prepared. Tracing by hand was manually done, and computer assisted overlay comparison was carried out. Results: Out of 2500 cross matches, expected result should have been 50 true positives and 2450 true negatives. In our study there were 38 true positive, 2406 true negatives, 44 false positive and 12 false negative matches in maxillary comparison, 44 true positive, 2424 true negatives, 26 false positive and 6 false negative matches in mandibular comparison and 31 true positive, 2446 true negatives, 4 false positive and 19 false negative matches when complete dentition (maxillary and mandibular) comparison was done. Hence this method showed significantly high false positive and true negative cases. Conclusion: We conclude that this computer assisted hand tracing overlay method for bite mark analysis helps in arriving at an exclusion rather than inclusion type of identification, owing to its high true negative cases.

The accuracy of the scintigraphic diagnosis of acute myocardial infarction with 99mTc-pyrophosphate, 99mTc-tetracycline and 99mTc-glucoheptonate was assessed in 63 patients, 43 of whom had clinical evidence of acute myocardial infarction. In 15, studies with both 99mTc-tetracycline and 99mTc-pyrophosphate were performed. Accuracy was greatest with 99mTc-pyrophosphate (17/17 true positives, 8/10 true negatives) contrasted with 99mTc-tetracycline (12/25 true positives, 6/11 true negatives) and 99mTc-glucoheptonate (3/13 true positives, 2/2 true negatives). 99mTc-pyrophosphate was the most sensitive tracer for the detection of acute myocardial infarction. The diagnostic accuracy with 99mTc-glucoheptonate was poor.

The aim of this study was to estimate the incremental budget impact (IBI) of a rapid diagnostic test to detect G6PDd in male patients infected with Plasmodium vivax in the Brazilian Amazon, as compared with the routine protocol recommended in Brazil which does not include G6PDd testing. The budget impact analysis was performed from the perspective of the Brazilian health system, in the Brazilian Amazon for the years 2013, 2014 and 2015. The analysis used a decision model to compare two scenarios: the first consisting of the routine recommended in Brazil which does not include prior diagnosis of dG6PD, and the second based on the use of RDT CareStart™ G6PD (CS-G6PD) in all male subjects diagnosed with vivax malaria. The expected implementation of the diagnostic test was 30% in the first year, 70% the second year and 100% in the third year. The analysis identified negative IBIs which were progressively smaller in the 3 years evaluated. The sensitivity analysis showed that the uncertainties associated with the analytical model did not significantly affect the results. A strategy based on the use of CS-G6PD would result in better use of public resources in the Brazilian Amazon.

Expanded newborn screening (NBS) for genetic disorders has improved diagnosis of numerous treatable diseases, positively impacting children's health outcomes. However, research about the psychological impact of expanded NBS on families, especially mothers, has been mixed. Our study examined associations between maternal experiences of expanded NBS and subsequent psychosocial functioning and parenting stress in mothers whose infants received either true negative (TN), true positive (TP) or false positive (FP) results after a 4- to 6-month period. The Parenting Stress Index and the Depression, Anxiety and Stress Scale were used to assess symptoms of anxiety, stress and depression in 3 sets of mothers, whose infants received TN (n = 31), TP (n = 8) or FP (n = 18) results. Multivariate analyses of variance (MANOVA) results revealed no significant differences among these three groups of mothers regarding overall anxiety, stress and depression. However, FP mothers experienced lower levels of stress related to their own health compared to TN group. Two potential trends were also identified; results suggested TN mothers might experience higher levels of isolation than mothers in the TP group and that FP mothers might report higher stress levels in relation to spousal relationships compared to the TN group. FP mothers seemed to report similar or better levels of psychosocial functioning than TN mothers. Our findings are encouraging with respect to impacts of NBS on maternal well-being. We also identify key areas for improvement (parental education) and research (isolation and spousal relationships).

Rationale: Studies of bronchoscopy have reported diagnostic yield (DY) using different calculation methods, which has hindered comparisons across studies. Objectives: To quantify the effect of the variability of four methods on DY estimates of bronchoscopy. Methods: We performed a simulation-based analysis of patients undergoing bronchoscopy using variations around base case assumptions for cancer prevalence (60%), distribution of nonmalignant findings, and degree of follow-up information at a fixed sensitivity of bronchoscopy for malignancy (80%). We calculated DY, the rate of true positives and true negatives (TNs), using four methods. Method 1 considered malignant and specific benign findings at index bronchoscopy as true positives and TNs, respectively. Method 2 included nonspecific benign findings as TNs. Method 3 considered nonspecific benign findings cases as TNs only if follow-up confirmed benign disease. Method 4 counted all cases with a nonmalignant diagnosis as TNs if follow-up confirmed benign disease. A scenario analysis and probabilistic sensitivity analysis were conducted to demonstrate the effect of parameter estimates on DY. A change in DY of >10% was considered clinically meaningful. Results: Across all pairwise comparisons of the four methods, a DY difference of >10% was observed in 76.7% of cases (45,992 of 60,000 comparisons). Method 4 resulted in DY estimates that were >10% higher than estimates made with other methods in >90% of scenarios. Variation in cancer prevalence had a large effect on DY. Conclusions: Across a wide range of clinical scenarios, the categorization of nonmalignant findings at index bronchoscopy and cancer prevalence had the largest impact on DY. The large variability in DY estimates across the four methods limits the interpretation of bronchoscopy studies and warrants standardization.

Background: Standard of care for women with a positive sentinel lymph node biopsy (SLNB) is to have a completion axillary lymph node dissection (cALND). For women with a negative SLNB, cALND is often not performed, accepting that a proportion will have a false negative (FN) result. FN rates are commonly reported based on surgeon experience. In the absence of cALND, information on FN rates will not be available, and other means of assessing the risk for FN SLNB is needed.Materials and Methods: Between May 1999 and December 2006, 1661 women with early-stage breast cancer that had undergone SLNB followed by cALND, were identified from our provincial database: 77 FN, 560 true positive (TP), and 1024 true negative (TN). FN cases were matched 1:3 with TN cases by date of SLNB. Chi-square and Wilcoxon Rank-sum tests were used to screen variables and those with moderate association were identified and included in subsequent models. Logistic regression was used to develop a multivariable model to predict the probability of FN vs. TN status. ROC curves were used to estimate the optimal probability cut-off, at which sensitivity (SN) and specificity (SP) were maximized. The model's performance was then assessed using a cross-validation technique.Results: Factors examined that did not significantly affect FN vs. TN status rate included: age, body mass index, previous breast surgery, histology, estrogen receptor status, margin status, tumor palpability, injection technique (peritumoral, periareolar), mapping agent used (yes/no), and SLNB done pre vs. post breast surgery (all p=NS). Factors identified that significantly affected FN vs. TN status (p&amp;lt;0.05) and thus included for potential use in the model included: tumor size, tumor grade, lymphovascular invasion (+/-LVI), tumor site (central/medial, lateral, other), type of breast surgery (mastectomy vs. lumpectomy), pre-operative lymphoscintiscan (yes/no), colloid (yes/no), number of SLN (1 vs. &amp;gt;1). The final model contained 5 variables: T stage (1 vs. 2), tumor grade, number of SLN removed, tumor site, and LVI. ROC identified an optimal probability cut-point for this model of 0.217 (21.7% risk of FN) with a corresponding SN of 71% and SP of 70%. In the cross-validation, the model correctly classified 66% of cases (SN of 73%, SP of 64%) with an AUC of 0.76. With increasing FN risk, SN declined and SP increased such that at a FN risk of 30%, this model had a SN 56%, SP 77%, and accuracy 72%. Using this model a woman with a T1, lateral, grade 3, 1 SLN and LVI- had a predicted FN risk of 21.5%, increasing to 52.2% if she were LVI+.Discussion: For women with early breast cancer, a negative SLNB result has a significant impact on prognosis and recommendations for further systemic and radiation therapy, this model (T size, tumor grade, number of SLN removed, tumor site, and LVI) is the first that would offer a quantitative prediction of FN risk in this setting, which could influence further discussion and therapeutic decision making. Potential refinements of this model will be explored, incorporating 'lower-priority' variables. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 303.

To evaluate the accuracy of diagnosing N3 disease using positron emission tomography (PET) with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) in patients with pulmonary disease. Twenty patients diagnosed as FDG-PET N3 were enrolled. On FDG-PET, lymph nodes were considered to be positive when increased uptake as compared with that of the surrounding mediastinum was visually observed, or the mean standardized uptake ratio (SUR) was more than 2, 2.5, or 3. On CT, lymph nodes exceeding 1 cm in the shortest diameter were regarded as positive. The PET result was true positive (TP) in 2 patients and false positive (FP) in 18 with an overall accuracy (OA) of 10% using visual criteria. Using an SUR of more than 2.5, the result was TP in 2, FP in 3, and true negative (TN) in 15, the false negative (FN) in 0, with an OA of 85%. CT diagnosis was TP in 2, FP in 9, and TN in 9 with an OA of 55%. The accuracy using the SUR criteria of more than 2.5 was superior to that of CT. Of 20 patients with the diagnosis of PET N3, we found frequent over-diagnosis in nodal staging using the visual criteria.

PurposeTo accomplish the 3D dose verification to IMRT plan by incorporating DVH information and gamma passing rates (GPs) (DVH_GPs) so as to better correlate the patient‐specific quality assurance (QA) results with clinically relevant metrics.Materials and methodsDVH_GPs analysis was performed to specific structures of 51 intensity‐modulated radiotherapy (IMRT) treatment plans (17 plans each for oropharyngeal neoplasm, esophageal neoplasm, and cervical neoplasm) with Delta4 3D dose verification system. Based on the DVH action levels of 5% and GPs action levels of 90% (3%/2 mm), the evaluation results of DVH_GPs analysis were categorized into four regions as follows: the true positive (TP) (%DE> 5%, GPs < 90%), the false positive (FP) (%DE ≤ 5%, GPs < 90%), the false negative (FN) (%DE> 5%, GPs ≥ 90%), and the true negative (TN) (%DE ≤ 5%, GPs ≥ 90%). Considering the actual situation, the final patient‐specific QA determination was made based on the DVH_GPs evaluation results. In order to exclude the impact of Delta4 phantom on the DVH_GPs evaluation results, 5 cm phantom shift verification was carried out to structures with abnormal results (femoral heads, lung, heart).ResultsIn DVH_GPs evaluation, 58 cases with FN, 5 cases with FP, and 2 cases with TP were observed. After the phantom shift verification, the extremely abnormal FN of both lung (%DE = 21.52%±8.20%) and heart (%DE = 19.76%) in the oropharyngeal neoplasm plans and of the bilateral formal heads (%DE = 26.41%±13.45%) in cervical neoplasm plans disappeared dramatically. DVH_GPs analysis was performed to all evaluation results in combination with clinical treatment criteria. Finally, only one TP case from the oropharyngeal neoplasm plans and one FN case from the esophageal neoplasm plans did not meet the treatment requirements, so they needed to be replanned.ConclusionThe proposed DVH_GPs evaluation method first make up the deficiency of conventional gamma analysis regarding intensity information and space information. Moreover, it improves the correlation between the patient‐specific QA results and clinically relevant metrics. Finally, it can distinguish the TP, TN, FP, and FN in the evaluation results. They are affected by many factors such as the action levels of DVH and GPs, the feature of the specific structure, the QA device, etc. Therefore, medical physicist should make final patient‐specific QA decision not only by taking into account the information of DVH and GPs, but also the practical situation.

To examine whether the use of sex-specific norms and cut scores to identify memory impairment improves diagnostic accuracy of amnestic mild cognitive impairment (aMCI) compared to non-sex-specific (typical) norms/cut scores given the female advantage in verbal memory. We calculated sex-specific and typical norms/cut scores (age and education specific) for impairment on the Rey Auditory Verbal Learning Test in the Mayo Clinic Study of Aging. Norms/cut scores were applied to 453 women and 532 men from the Alzheimer's Disease Neuroimaging Initiative. We compared sex differences in rates of aMCI (Jak/Bondi criteria) for sex-specific vs typical norms/cut scores. Using sex-specific cut scores as the true condition and typical cut scores as the predicted condition, we categorized participants as true positives (TPs), false positives (FPs), true negative (TNs), or false negative (FNs). In cross-sectional analyses within sex, we compared positivity rates of CSF hyperphosphorylated tau/β-amyloid (Aβ) and cortical Aβ deposition ([18F]AV45 PET) and APOE ε4 frequency among diagnostic comparison groups. The frequency of aMCI was higher in men when using typical norms/cut scores. Using sex-adjusted norms/cut scores led to the identification of 10% FNs (missed aMCI cases) among women and 10% FPs among men. Biomarker analyses supported the hypothesis that sex-specific diagnostic criteria improves diagnostic accuracy. Biomarkers rates were higher in FNs vs TNs and similar in FNs and TPs. Biomarker rates were lower in FPs vs TPs and similar between FPs and TNs. Results suggest that non-sex-specific aMCI diagnostic criteria led to a 20% diagnostic error rate. Accounting for sex differences in verbal memory performance may improve aMCI classification.

A hierarchical shape description approach and its application in similarity measurement of polygon entities