HAMAP in 2015: updates to the protein family classification and annotation system

HAMAP (High-quality Automated and Manual Annotation of Proteins—available at http://hamap.expasy.org/) is a system for the automatic classification and annotation of protein sequences. HAMAP provides annotation of the same quality and detail as UniProtKB/Swiss-Prot, using manually curated profiles for protein sequence family classification and expert curated rules for functional annotation of family members. HAMAP data and tools are made available through our website and as part of the UniRule pipeline of UniProt, providing annotation for millions of unreviewed sequences of UniProtKB/TrEMBL. Here we report on the growth of HAMAP and updates to the HAMAP system since our last report in the NAR Database Issue of 2013. We continue to augment HAMAP with new family profiles and annotation rules as new protein families are characterized and annotated in UniProtKB/Swiss-Prot; the latest version of HAMAP (as of 3 September 2014) contains 1983 family classification profiles and 1998 annotation rules (up from 1780 and 1720). We demonstrate how the complex logic of HAMAP rules allows for precise annotation of individual functional variants within large homologous protein families. We also describe improvements to our web-based tool HAMAP-Scan which simplify the classification and annotation of sequences, and the incorporation of an improved sequence-profile search algorith

HAMAP in 2013, new developments in the protein family classification and annotation system

HAMAP (High-quality Automated and Manual Annotation of Proteins—available at http://hamap.expasy.org/) is a system for the classification and annotation of protein sequences. It consists of a collection of manually curated family profiles for protein classification, and associated annotation rules that specify annotations that apply to family members. HAMAP was originally developed to support the manual curation of UniProtKB/Swiss-Prot records describing microbial proteins. Here we describe new developments in HAMAP, including the extension of HAMAP to eukaryotic proteins, the use of HAMAP in the automated annotation of UniProtKB/TrEMBL, providing high-quality annotation for millions of protein sequences, and the future integration of HAMAP into a unified system for UniProtKB annotation, UniRule. HAMAP is continuously updated by expert curators with new family profiles and annotation rules as new protein families are characterized. The collection of HAMAP family classification profiles and annotation rules can be browsed and viewed on the HAMAP website, which also provides an interface to scan user sequences against HAMAP profile

Prohormones in the early diagnosis of cardiac syncope

Background--The early detection of cardiac syncope is challenging. We aimed to evaluate the diagnostic value of 4 novel prohormones, quantifying different neurohumoral pathways, possibly involved in the pathophysiological features of cardiac syncope: midregional-pro-A-type natriuretic peptide (MRproANP), C-terminal proendothelin 1, copeptin, and midregionalproadrenomedullin. Methods and Results--We prospectively enrolled unselected patients presenting with syncope to the emergency department (ED) in a diagnostic multicenter study. ED probability of cardiac syncope was quantified by the treating ED physician using a visual analogue scale. Prohormones were measured in a blinded manner. Two independent cardiologists adjudicated the final diagnosis on the basis of all clinical information, including 1-year follow-up. Among 689 patients, cardiac syncope was the adjudicated final diagnosis in 125 (18%). Plasma concentrations of MRproANP, C-terminal proendothelin 1, copeptin, and midregional-proadrenomedullin were all significantly higher in patients with cardiac syncope compared with patients with other causes (P < 0.001). The diagnostic accuracies for cardiac syncope, as quantified by the area under the curve, were 0.80 (95% confidence interval [CI], 0.76-0.84), 0.69 (95% CI, 0.64-0.74), 0.58 (95% CI, 0.52-0.63), and 0.68 (95% CI, 0.63-0.73), respectively. In conjunction with the ED probability (0.86; 95% CI, 0.82-0.90), MRproANP, but not the other prohormone, improved the area under the curve to 0.90 (95% CI, 0.87-0.93), which was significantly higher than for the ED probability alone (P=0.003). An algorithm to rule out cardiac syncope combining an MRproANP level of < 77 pmol/L and an ED probability of < 20% had a sensitivity and a negative predictive value of 99%. Conclusions--The use of MRproANP significantly improves the early detection of cardiac syncope among unselected patients presenting to the ED with syncope

On the derived category of a graded commutative noetherian ring

For any graded commutative noetherian ring, where the grading group is abelian and where commutativity is allowed to hold in a quite general sense, we establish an inclusion-preserving bijection between, on the one hand, the twist-closed localizing subcategories of the derived category, and, on the other hand, subsets of the homogeneous spectrum of prime ideals of the ring. We provide an application to weighted projective schemes.Comment: 19 pages; minor corrections, added a few detail

Clinical effect of obesity on N-terminal pro-B-type natriuretic peptide cut-off concentrations for the diagnosis of acute heart failure

AIMS Obese patients have lower natriuretic peptide concentrations. We hypothesized that adjusting the concentration of N-terminal pro-B-type natriuretic peptide (NT-proBNP) for obesity could further increase its clinical utility in the early diagnosis of acute heart failure (AHF). METHODS AND RESULTS This hypothesis was tested in a prospective diagnostic study enrolling unselected patients presenting to the emergency department with acute dyspnoea. Two independent cardiologists/internists centrally adjudicated the final diagnosis using all individual patient information including cardiac imaging. NT-proBNP plasma concentrations were applied: first, using currently recommended cut-offs; second, using cut-offs lowered by 33% with body mass index (BMI) of 30-34.9 kg/m$^{2}$ and by 50% with BMI ≥ 35 kg/m$^{2}$ . Among 2038 patients, 509 (25%) were obese, of which 271 (53%) had AHF. The diagnostic accuracy of NT-proBNP as quantified by the area under the receiver-operating characteristic curve was lower in obese versus non-obese patients (0.890 vs. 0.938). For rapid AHF rule-out in obese patients, the currently recommended cut-off of 300 pg/ml achieved a sensitivity of 96.7% (95% confidence interval [CI] 93.8-98.2%), ruling out 29% of patients and missing 9 AHF patients. For rapid AHF rule-in, the age-dependent cut-off concentrations (age 75 years: 1800 pg/ml) achieved a specificity of 84.9% (95% CI 79.8-88.9%). Proportionally lowering the currently recommended cut-offs by BMI increased sensitivity to 98.2% (95% CI 95.8-99.2%), missing 5 AHF patients; reduced the proportion of AHF patients remaining in the 'gray zone' (48% vs. 26%; p = 0.002), achieving a specificity of 76.5% (95% CI 70.7-81.4%). CONCLUSIONS Adjusting NT-proBNP concentrations for obesity seems to further increase its clinical utility in the early diagnosis of AHF

Cardiac myosin-binding protein C in the diagnosis and risk stratification of acute heart failure

Cardiac myosin-binding protein C (cMyC) seems to be even more sensitive in the quantification of cardiomyocyte injury vs. high-sensitivity cardiac troponin, and may therefore have diagnostic and prognostic utility.; In a prospective multicentre diagnostic study, cMyC, high-sensitivity cardiac troponin T (hs-cTnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma concentrations were measured in blinded fashion in patients presenting to the emergency department with acute dyspnoea. Two independent cardiologists centrally adjudicated the final diagnosis. Diagnostic accuracy for acute heart failure (AHF) was quantified by the area under the receiver operating characteristic curve (AUC). All-cause mortality within 360 days was the prognostic endpoint. Among 1083 patients eligible for diagnostic analysis, 51% had AHF. cMyC concentrations at presentation were higher among AHF patients vs. patients with other final diagnoses [72 (interquartile range, IQR 39-156) vs. 22 ng/L (IQR 12-42), P < 0.001)]. cMyC's AUC was high [0.81, 95% confidence interval (CI) 0.78-0.83], higher than hs-cTnT's (0.79, 95% CI 0.76-0.82, P = 0.081) and lower than NT-proBNP's (0.91, 95% CI 0.89-0.93, P < 0.001). Among 794 AHF patients eligible for prognostic analysis, 28% died within 360 days; cMyC plasma concentrations above the median indicated increased risk of death (hazard ratio 2.19, 95% CI 1.66-2.89; P < 0.001). cMyC's prognostic accuracy was comparable with NT-proBNP's and hs-cTnT's. cMyC did not independently predict all-cause mortality when used in validated multivariable regression models. In novel multivariable regression models including medication, age, left ventricular ejection fraction, and discharge creatinine, cMyC remained an independent predictor of death and had no interactions with medical therapies at discharge.; Cardiac myosin-binding protein C may aid physicians in the rapid triage of patients with suspected AHF

A 0/1h-algorithm using cardiac myosin-binding protein C for early diagnosis of myocardial infarction.

AIMS Cardiac myosin-binding protein C (cMyC) demonstrated high diagnostic accuracy for the early detection of non-ST-elevation myocardial infarction (NSTEMI). Its dynamic release kinetics may enable a 0/1h-decision algorithm that is even more effective than the ESC hs-cTnT/I 0/1 h rule-in/rule-out algorithm. METHODS AND RESULTS In a prospective international diagnostic study enrolling patients presenting with suspected NSTEMI to the emergency department, cMyC was measured at presentation and after 1 h in a blinded fashion. Modelled on the ESC hs-cTnT/I 0/1h-algorithms, we derived a 0/1h-cMyC-algorithm. Final diagnosis of NSTEMI was centrally adjudicated according to the 4th Universal Definition of Myocardial Infarction. Among 1495 patients, the prevalence of NSTEMI was 17%. The optimal derived 0/1h-algorithm ruled-out NSTEMI with cMyC 0 h concentration below 10 ng/L (irrespective of chest pain onset) or 0 h cMyC concentrations below 18 ng/L and 0/1 h increase <4 ng/L. Rule-in occurred with 0 h cMyC concentrations of at least 140 ng/L or 0/1 h increase ≥15 ng/L. In the validation cohort (n = 663), the 0/1h-cMyC-algorithm classified 347 patients (52.3%) as 'rule-out', 122 (18.4%) as 'rule-in', and 194 (29.3%) as 'observe'. Negative predictive value for NSTEMI was 99.6% [95% confidence interval (CI) 98.9-100%]; positive predictive value 71.1% (95% CI 63.1-79%). Direct comparison with the ESC hs-cTnT/I 0/1h-algorithms demonstrated comparable safety and even higher triage efficacy using the 0h-sample alone (48.1% vs. 21.2% for ESC hs-cTnT-0/1 h and 29.9% for ESC hs-cTnI-0/1 h; P < 0.001). CONCLUSION The cMyC 0/1h-algorithm provided excellent safety and identified a greater proportion of patients suitable for direct rule-out or rule-in based on a single measurement than the ESC 0/1h-algorithm using hs-cTnT/I. TRIAL REGISTRATION ClinicalTrials.gov number, NCT00470587

External Validation and Extension of a Clinical Score for the Discrimination of Type 2 Myocardial Infarction

Background: The early non-invasive discrimination of Type 2 versus Type 1 Myocardial Infarction (T2MI, T1MI) is a major unmet clinical need. We aimed to externally validate a recently derived clinical score (Neumann) combing female sex, no radiating chest pain, and high-sensitivity cardiac troponin I (hs-cTnI) concentration ≤40.8 ng/L. Methods: Patients presenting with acute chest discomfort to the emergency department were prospectively enrolled into an international multicenter diagnostic study. The final diagnoses of T2MI and T1MI were centrally adjudicated by two independent cardiologists using all information including cardiac imaging and serial measurements of hs-cTnT/I according to the fourth universal definition of MI. Model performance for T2MI diagnosis was assessed by formal tests and graphical means of discrimination and calibration. Results: Among 6684 enrolled patients, MI was the adjudicated final diagnosis in 1079 (19%) patients, of which 242 (22%) had T2MI. External validation of the Neumann Score showed a moderate discrimination (C-statistic 0.67 (95%CI 0.64–0.71)). Model calibration showed underestimation of the predicted probabilities of having T2MI for low point scores. Model extension by adding the binary variable heart rate >120/min significantly improved model performance (C-statistic 0.73 (95% CI 0.70–0.76, p 120/min improved the model’s performance