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PubMed2004

A cross-validation of safety climate scale using confirmatory factor analytic approach.

PROBLEM: Given the lack of a consistent factor structure of safety climate, this study tested the stability of a factor structure of a safety climate scale developed through an extensive literature review using confirmatory factor analytic approach and cross-validation. METHODS: A cross-sectional sample of 722 U.S. grain industry workers participated in the questionnaire survey. RESULTS: The safety climate scale developed through the generation of an item pool based on a table of specifications, subsequent scientific item reduction procedures, reviews from experts, and pilot test yielded adequate reliabilities for each dimension. Each item showed proper discriminative power based on both internal and external criteria. Criterion validity was manifested by the significant positive correlation of the scale with five criteria. Evidence of construct validity was provided by both exploratory and confirmatory factor analyses. Both calibration and validation samples supported a consistent factor structure. Management commitment and supervisor support were found to influence other dimensions of safety climate. DISCUSSION: This study provides an insight into the primary reason why previous attempts have failed to find a consistent factor structure of safety climate: No specification of the influence of management commitment and supervisor support on other dimensions of safety in their models. IMPACT ON INDUSTRY: The findings of this study provide a framework upon which accident prevention efforts can be effectively organized and underscore the importance of management commitment and supervisor support as they affect employee safety perceptions.

Adult↗
PubMed2026

Advancing cancer detection and treatment using longitudinal routine clinical data.

Cancer management remains fragmented across its continuum, from late-stage diagnosis and salvage therapies to non-personalized surveillance. Here, we present Oncoformer, a unified multimodal transformer model trained on the China Oncology Multimodal Prediction and Surveillance Study (COMPASS) cohort (3.67 million individuals, 17.7 million clinical visits) and validated on independent external cohorts, including the UK Biobank. Oncoformer integrates longitudinal electronic health records with chest X-ray imaging to address multiple clinical tasks: pan-cancer diagnosis (area under the receiver operating characteristic curve [AUROC] = 0.956), future cancer prediction up to 1 year before diagnosis (AUROC = 0.869), tumor stage inference (mean AUROC > 0.90), patient-specific treatment-response forecasting, and recurrence-free survival stratification across ten cancer types (all p < 0.01). Staging predictions were independently validated against postoperative pathological endpoints and shown to converge on core cancer genomic pathways. By translating routine clinical data into a dynamic view of cancer evolution, Oncoformer provides a framework for risk-informed cancer prediction and treatment stratification using routine clinical data.

Humans↗
PubMed2026

Integrative multi-omics analysis unravels the metabolic landscape and reveals serum biomarkers for early diagnosis of hyperuricemia.

BACKGROUND: Hyperuricemia (HUA) is a major risk factor for gout and multiple metabolic disorders. Although serum uric acid (UA) is the gold standard for HUA diagnosis, it fails to reflect early metabolic disturbances and shows limited predictive value for asymptomatic HUA. This study sought to elucidate the pathological mechanisms underlying HUA and identify novel diagnostic biomarkers beyond UA. METHODS: This study enrolled 195 patients with HUA and 98 healthy controls. Global metabolomics and proteomics profiling were performed to characterize molecular alterations underlying HUA. Based on the biological relevance of the shared dysregulated pathways, a pathway correlation network was constructed to elucidate the pathological mechanisms driving HUA initiation and progression. Furthermore, diagnostic biomarkers for HUA were identified using machine learning algorithms, and were validated with an external cohort. RESULTS: HUA patients exhibited distinct metabolic and proteomic profiles compared with healthy controls. Integrated multi-omics pathway analysis revealed that peroxisome proliferators-activated receptor signaling pathway, arachidonic acid metabolism, purine metabolism, pyrimidine metabolism and sphingolipid signaling pathway were significantly dysregulated in HUA. Among them, arachidonic acid metabolism was identified as a hub pathway involved in HUA progression. Furthermore, a metabolite panel consisting of cysteine-S-sulfate, glycerophosphocholine and 4-hydroxyphenylpyruvic acid was screened by machine learning and validated in an independent cohort, which showed slightly higher diagnostic performance for HUA than UA. CONCLUSIONS: This study reveals the core metabolic and protein regulatory networks of HUA, and identifies a novel serum metabolite panel for the diagnosis of HUA. These findings provide new insights for improved clinical diagnosis and management.

Humans↗
PubMed2026

Mitochondria related gene signature serves as prognosis prediction and risk stratification of cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CHOL) is a highly aggressive biliary malignancy with poor clinical outcomes and limited effective prognostic biomarkers. Mitochondrial dysfunction participates in multiple oncological processes of CHOL, yet the prognostic roles of mitochondria&#x2011;related genes (MRGs) remain poorly understood. This study aimed to characterize MRGs expression in CHOL and develop a molecular prognostic model for predicting patient survival and guiding clinical management. METHODS: RNA sequencing (RNA-seq) and clinical data of CHOL were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) (GSE89748) databases. Differentially expressed MRGs were identified, and 10 machine learning algorithms were used to construct prognostic models. The optimal model (highest average C-index) was selected to establish a mitochondria-related risk score (MRRS), which was validated internally and externally. A nomogram integrating clinical factors and MRRS was developed, and biological mechanisms were explored via functional and immune analyses. RESULTS: A 3-MRG (MAP3K1, MRPL18, PYGB) prognostic signature was constructed, stratifying patients into high- and low-risk groups with significantly different overall survival. The model showed high predictive accuracy, with an area under the curve (AUC) up to 0.845, and MRRS was an independent prognostic factor. The signature was associated with mitochondrial pathways, and the high-risk group had distinct immune infiltration and mutation profiles. CONCLUSIONS: A validated MRG prognostic model effectively stratifies CHOL patients and has potential clinical value for prognosis prediction. Further validation in larger cohorts is needed to confirm its applicability.

Cholangiocarcinoma (CHOL)↗
PubMed2005

Validation of a postresection pancreatic adenocarcinoma nomogram for disease-specific survival.

PURPOSE: Nomograms are statistically based tools that provide the overall probability of a specific outcome. They have shown better individual discrimination than the current TNM staging system in numerous patient tumor models. The pancreatic nomogram combines individual clinicopathologic and operative data to predict disease-specific survival at 1, 2, and 3 years from initial resection. A single US institution database was used to test the validity of the pancreatic adenocarcinoma nomogram established at Memorial Sloan-Kettering Cancer Center. PATIENTS AND METHODS: The nomogram was created from a prospective pancreatic adenocarcinoma database that included 555 consecutive patients between October 1983 and April 2000. The nomogram was validated by an external patient cohort from a retrospective pancreatic adenocarcinoma database at Massachusetts General Hospital that included 424 consecutive patients between January 1985 and December 2003. RESULTS: Of the 424 patients, 375 had all variables documented. At last follow-up, 99 patients were alive, with a median follow-up time of 27 months (range, 2 to 151 months). The 1-, 2-, and 3-year disease-specific survival rates were 68% (95% CI, 63% to 72%), 39% (95% CI, 34% to 44%), and 27% (95% CI, 23% to 32%), respectively. The nomogram concordance index was 0.62 compared with 0.59 with the American Joint Committee on Cancer (AJCC) stage (P = .004). This suggests that the nomogram discriminates disease-specific survival better than the AJCC staging system. CONCLUSION: The pancreatic cancer nomogram provides more accurate survival predictions than the AJCC staging system when applied to an external patient cohort. The nomogram may aid in more accurately counseling patients and in better stratifying patients for clinical trials and molecular tumor analysis.

Adenocarcinoma↗
PubMedDate not supplied

Combinatorial QSAR of ambergris fragrance compounds.

A combinatorial quantitative structure-activity relationships (Combi-QSAR) approach has been developed and applied to a data set of 98 ambergris fragrance compounds with complex stereochemistry. The Combi-QSAR approach explores all possible combinations of different independent descriptor collections and various individual correlation methods to obtain statistically significant models with high internal (for the training set) and external (for the test set) accuracy. Seven different descriptor collections were generated with commercially available MOE, CoMFA, CoMMA, Dragon, VolSurf, and MolconnZ programs; we also included chirality topological descriptors recently developed in our laboratory (Golbraikh, A.; Bonchev, D.; Tropsha, A. J. Chem. Inf. Comput. Sci. 2001, 41, 147-158). CoMMA descriptors were used in combination with MOE descriptors. MolconnZ descriptors were used in combination with chirality descriptors. Each descriptor collection was combined individually with four correlation methods, including k-nearest neighbors (kNN) classification, Support Vector Machines (SVM), decision trees, and binary QSAR, giving rise to 28 different types of QSAR models. Multiple diverse and representative training and test sets were generated by the divisions of the original data set in two. Each model with high values of leave-one-out cross-validated correct classification rate for the training set was subjected to extensive internal and external validation to avoid overfitting and achieve reliable predictive power. Two validation techniques were employed, i.e., the randomization of the target property (in this case, odor intensity) also known as the Y-randomization test and the assessment of external prediction accuracy using test sets. We demonstrate that not every combination of the data modeling technique and the descriptor collection yields a validated and predictive QSAR model. kNN classification in combination with CoMFA descriptors was found to be the best QSAR approach overall since predictive models with correct classification rates for both training and test sets of 0.7 and higher were obtained for all divisions of the ambergris data set into the training and test sets. Many predictive QSAR models were also found using a combination of kNN classification method with other collections of descriptors. The combinatorial QSAR affords automation, computational efficiency, and higher probability of identifying significant QSAR models for experimental data sets than the traditional approaches that rely on a single QSAR method.

Algorithms↗
PubMed2002

Body fat standards and individual physical readiness in a randomized Army sample: screening weights, methods of fat assessment, and linkage to physical fitness.

Body fat standards have been used by the military services since the early 1980s to prevent obesity and motivate good fitness habits. The Army Weight Control Program has continued to undergo evaluation and incorporate improvements based on emerging scientific findings. Recently drafted revisions of Department of Defense-wide procedures address issues of consistency and validity raised by external oversight groups. This study evaluated the impact of three proposed refinements of the Army Weight Control Program. Anthropometric measurements and fitness test performance were obtained in a randomized sample of 1,038 male and 347 nonpregnant female soldiers at three Army posts. Of this sample, 11% of men and 17% of women were overweight and overfat; 6.3 and 9.8%, respectively, were currently on the Army Weight Control Program. Screening weight tables that ensure women are not inappropriately striving to meet weights more stringent than "healthy" weight (i.e., body mass index < 25 kg/m2) still correctly identified all women for evaluation for the age-specific body fat standards. Body fat estimation using more valid DoD body fat equations that include an abdominal circumference for women reduced the number of female soldiers currently classified as exceeding fat standards, coincidentally resulting in a comparable prevalence of male and female soldiers over the fat standards (12%). A body fat allowance for young soldiers who scored very well on the physical fitness test could have benefited one-fourth of the soldiers exceeding fat standards and acknowledges biological variability in body fat thresholds. Whereas this linkage may motivate fitness habits, it complicates enforcement of reasonably achievable body fat standards. The proposed changes in fat screening and measurement methods are appropriate, but the impact to health and physical readiness of the Force cannot be accurately predicted or measured because of the absence of comprehensive baseline data and tracking mechanisms.

Adult↗
PubMed2004

Development and validation of an instrument to measure the effects of a mistletoe preparation on quality of life of cancer patients: the Life Quality Lectin-53 (LQL-53) Questionnaire.

Mistletoe preparations standardised to the content of mistletoe lectin are supposed to improve quality of life (QoL) in patients with cancer. To obtain a validated and sensitive research instrument, the Life Quality Lectin-53 (LQL-53) Questionnaire was developed in three phases: item generation via interviews with 42 patients, item selection by means of a study with 109 cancer patients, and psychometric testing. The LQL-53 includes 46 items assigned to the subscales 'General well-being', 'Emotional well-being', 'Vitality' 'Hope', 'Locus of control', Social relationships', and 'Physical complaints', plus seven items dealing with possible adverse effects of mistletoe treatment. Psychometric testing was carried out in a study with 112 patients with solid tumours who were treated with a mistletoe preparation standardised to mistletoe lectins for 12 weeks. Internal consistency (Cronbach's alpha) was between 0.72 and 0.94. Test-retest reliability was > or = r of 0.72. Subscales correlated highly with external criteria. Construct validity, as determined by Multitrait Scaling Analysis, resulted in an optimal assignment of items to subscales (scaling success) for four of the subscales. During the course of the therapy, significant improvement in QoL was found in all subscales. In two of the subscales, effect size was high (>0.80), and in five other subscales it varied between 0.53 and 0.78.

Adjuvants, Immunologic↗
PubMed2006

Reliability of respiratory tidal volume estimation by means of ambulatory inductive plethysmography.

Ambulatory monitoring of ventilatory parameters in everyday life, field research and clinical situations may offer new insights into respiratory functioning in health and disease. Recent technological advances that employ ambulatory inductive plethysmography could make monitoring of respiration outside the clinic and laboratory feasible. Inductive plethysmography provides a method for nonintrusive assessment of both timing (e.g. respiration rate) and volumetric parameters (e.g. tidal volume and minute ventilation), by which tidal volume is initially calibrated to direct measures of volume. Estimates of tidal volume assessed by this technique have been validated in laboratory investigations, usually examining within-individual relations to direct measures over a large range of tidal volume variation. However, the reliability of individual differences in tidal volume or other breathing parameters has not been tested under naturalistic measurement conditions using inductive plethysmography. We examined the test-retest reliability of respiration rate, tidal volume and other volumetric parameters of breathing over a period of six weeks of repeated measurements during baseline conditions and breathing exercises with 16 healthy freely moving volunteers in a Yoga course. Reliability of measurement was evaluated by calculating the average week-to-week between-subject correlation coefficients for each physiological measure. Additionally because body-mass index has been previously positively correlated to tidal volume, we also assessed this relationship as an external criterion of validity of tidal volume estimation. Regarding the latter, similar correlations to those previous studies were found (r = 0.6). Furthermore, reliability estimates were high and consistent across respiratory measures (typically r's = 0.7-0.8). These results suggest the validity of ambulatory inductive plethysmographic measurement of respiration, at least under relatively sedentary conditions. Findings also point to the stability of individual differences in respiratory parameters over consecutive weeks.

Activities of Daily Living↗
PubMed2005

Validation of 1997 Partin Tables' lymph node invasion predictions in men treated with radical prostatectomy in Montreal Quebec.

OBJECTIVE: The accuracy of 1997 Partin Tables' lymph node invasion (LNI) predictions exhibits important variability in different testing populations. We explored the LNI predictive accuracy in radical prostatectomy (RP) patients from Montreal, Canada. Moreover, we assessed the extent of change in predictive accuracy related to a modification of PSA coding from categorical to continuous. METHODS: We used pretreatment serum PSA, clinical stage, and biopsy Gleason sum from 537 men treated with RP to compare predicted and observed rates of LNI. Accuracy was quantified with receiver-operating characteristics curves. RESULTS: Accuracy was 0.760 in 369 evaluable patients, when categorically coded pretreatment PSA (0-4, 4.1-10, 10.1-20, 20.1+) was combined with clinical stage and biopsy Gleason sum. A 2.7% accuracy increase was noted when categorically coded PSA was replaced with continuously coded values. CONCLUSION: Partin Tables' LNI predictions showed comparable accuracy to a community-based sample from the United States (0.766), and to a recent, multi-institutional sample (0.740). However, accuracy was lower than reported in internal (0.818), and external (0.837) academic, validation cohorts. Accuracy of LNI predictions was appreciably higher, when continuously coded PSA was used.

Humans↗
PubMed1995

[The assessment of individual differences in self-control in daily life].

Two studies were conducted to develop an instrument to assess individual differences in self-control in daily life. In Study 1, a 20-item Redressive-Reformative Self-Control Scale (RRS) was developed through a study involving 529 subjects. RRS consists of three sub-scales: "redressive self-control (RDSC)" which assesses a tendency of using a repertoire to resume normal functions that have been disrupted; "reformative self-control (RFSC)" which measures one's tendency to force oneself into a stressful situations for the sake of larger and more meaningful rewards in the future; and "external control". The validity of two sub-scales (RDSC, RFSC) was confirmed in Study 2. Fifty-one subjects selected on the basis of RDSC and RFSC scores were interviewed about self-control in their everyday lives. The findings indicated the importance of a combination of redressive and reformative functions in successful self-control. It was suggested that these two functions be examined for the assessment of individual differences in self-control in daily life.

Activities of Daily Living↗
PubMed2004

Construction and validation of a prognostic model across several studies, with an application in superficial bladder cancer.

Many models for clinical prediction (prognosis or diagnosis) are published in the medical literature every year but few such models find their way into clinical practice. The reason may be that since in most cases models have not been validated in independent data, they lack generality and/or credibility. In this paper we consider the situation in which several compatible, independent data sets relating to a given disease with a time-to-event endpoint are available for analysis. The aim is to construct and evaluate a single prognostic model. Building a multivariable model from the available prognostic factors is accomplished within the Cox proportional hazards framework, stratifying by study. Non-linear relationships with continuous predictors are modelled by using fractional polynomials. To assess the discrimination or separation of a survival model, we use the D statistic of Royston and Sauerbrei. D may be interpreted as the separation (log hazard ratio) between the survival distributions for two independent prognostic groups. To evaluate the generality of a prognostic model across the data sets, we propose 'internal-external cross-validation' on D: each study is omitted in turn, the model parameters are estimated from the remaining studies and D is evaluated in the omitted study. Because the linear predictor of a survival model tells only part of the story, we also suggest a method for investigating heterogeneity in the baseline distribution function across studies which involves fitting completely specified, flexible parametric survival models (Royston and Parmar). Our final models combine the prognostic index (obtained with stratification by study) with the pooled baseline survival distribution (estimated parametrically). By applying this methodology, we construct two prognostic scores in superficial bladder cancer. The simpler of the two scores is more suited to clinical application. We show that a three-group prognostic classification scheme based on either score produces well-separated survival curves for each of the data sets, despite identifiable heterogeneity among the baseline distribution functions and to a lesser extent among the prognostic indexes for the individual studies.

Adult↗
PubMed1996

Reliability of the recording of hysterectomy in the Saskatchewan health care system.

OBJECTIVE: To determine the validity of data pertaining to hysterectomy in the Saskatchewan health care utilisation datafiles. DESIGN: Retrospective analysis of routinely collected data covering hospital discharge records and practitioner claims for reimbursement of services, together with a review of clinical charts. SETTING: Province of Saskatchewan, Canada. SAMPLE: All 1905 cases of hysterectomy in one calendar year for analysis of datafiles and a random sample of 227 clinical charts for review. METHOD: Information in the hospitalisation datafile was validated through an external comparison with data extracted from a review of clinical charts, as well as an internal comparison with independent data from the practitioner claims file. Corresponding context data on drug use and performance of related procedures were also analysed. RESULTS: Concordance between hospital data and clinical charts was greater than 95% for those items of an administrative nature as well as type of hysterectomy and was around 85% for the diagnoses. When hospitalisation and practitioner claims data were compared, the concordance was 98% for type of hysterectomy but only 56% for diagnoses. CONCLUSIONS: The agreement between hospital data and clinical charts was excellent. The concordance between hospitalisation and practitioner claims data was almost exact for type of hysterectomy, while discrepancies in diagnoses between these files were mostly explainable on the basis of accepted clinical practice. Saskatchewan health care utilisation datafiles provide a source of valid data for research and evaluation studies.

Adolescent↗
PubMed2005

Development and validation of a new approach for computer-aided long bone fracture reduction using unilateral external fixator.

An innovative computer-aided method to plan and execute long bone fracture reduction using Dynafix unilateral external fixator (EF) is presented and validated. A matrix equation, which represents a sequential transformation from proximal to distal ends, was derived and solved for the amount of rotation and translation required at each EF joint to correct for a displaced fracture using a non-linear least square optimization method. Six polyurethane-foam models of displaced fracture tibiae were used to validate the method. The reduction accuracy was quantified by calculating the residual translations (xr, yr, zr), the residual displacement (dr), and the residual angulations (alphar, betar, gammar) based on the X-Y-Z Euler angle convention. The experiment showed that the mean+/-S.D. of alphar, betar, gammar, xr, yr, zr and dr were 1.57+/-1.14 degrees, 1.33+/-0.90 degrees, 0.71+/-0.70 degrees, 0.98+/-1.85, 0.80+/-0.67, 0.30+/-0.27, and 0.50+/-0.77 mm, respectively, which demonstrated the accuracy and reliability of the method. Instead of adjusting the fixator joints in-situ, our method allows for off-site adjustment of the fixator joints and employs the adjusted EF as a template to guide the surgeons to manipulate the fracture fragments to complete the reduction process. Success of this method would allow surgeons to perform fracture reduction more objectively, efficiently and accurately yet reduce the radiation exposure to both the involved clinicians and patients and lessen the extent of periosteum and soft tissue disruption around the fracture site.

Bone and Bones↗
PubMed1995

Quantitative three-dimensional reconstruction of aneurysmal left ventricles. In vitro and in vivo validation.

BACKGROUND: Current two-dimensional (2D) echocardiographic measures of left ventricular (LV) volume are most limited by aneurysmal distortion, which restricts application of simple geometric models that assume symmetrical shape. 2D methods also fail to provide separate volumes of the aneurysm and nonaneurysmal residual LV cavity, which could help assess the stroke volume wasted by dyskinesis and the potential residual LV body to guide surgical approaches and predict their outcome. Three-dimensional (3D) echocardiographic reconstruction has potential advantages for assessing aneurysmal left ventricles because it is not dependent on geometric assumptions, does not require standardized views that may exclude portions of the aneurysm, and can potentially measure separate aneurysm and nonaneurysm cavity volumes of any shape. The purpose of this study was first, to validate the accuracy of 3D echocardiographic reconstruction for quantifying total LV and separate LV body and aneurysm volumes in vitro so as to provide direct standards for the separate volumes; and second, to determine the feasibility and accuracy of 3D echocardiographic reconstruction for quantifying the total volume and function of aneurysmal left ventricles in an animal model, providing a reference standard for instantaneous LV volume. METHODS AND RESULTS: A recently developed 3D system that automatically combines 2D images and their locations was applied (1) to reconstruct 10 aneurysmal ventricular phantoms and 12 gel-filled autopsied human hearts with aneurysms, comparing cavity volumes (total and aneurysm) to those measured by fluid displacement; and (2) to reconstruct the left ventricle during 19 hemodynamic stages in four dogs with surgically created LV aneurysms, comparing total volumes with actual instantaneous values measured by an intracavitary balloon attached to an external column for validation and also calculating the stroke volume wasted by aneurysmal dyskinesis. 3D reconstruction reproduced the distorted aneurysmal LV shapes. In vitro, calculated volumes (aneurysm, nonaneurysm, and total) agreed well with actual values, with correlation coefficients of .99 and SEEs of 3.2 to 6.1 cm3 for phantoms and 3.4 to 4.2 cm3 for autopsied hearts (mean error, < 4% for both). In vivo, LV end-diastolic, end-systolic, and stroke volumes as well as ejection fraction calculated by 3D echocardiography correlated well with actual values (r = .99, .99, .95, and .99, respectively) and agreed closely with them (SEE = 4.3 cm3, 3.5 cm3, 1.7 cm3, and 2%, respectively). The stroke volumes wasted by the aneurysm were -20.1 +/- 19.3% of LV body (nonaneurysm) stroke volume. CONCLUSIONS: Despite distorted ventricular shapes, a recently developed 3D echocardiographic system and surfacing algorithm can accurately reconstruct aneurysmal left ventricles and quantify total LV volume (validated in vivo and in vitro) as well as the separate volumes of the aneurysm and residual LV body (validated in vitro). This should improve our ability to evaluate such ventricles and guide surgical approaches.

Algorithms↗
PubMed2001

Particle characterization and separation by a coupled acoustic-gravity field.

A coupled acoustic-gravity field is proposed as a novel external field for particle separation and characterization. When a standing plane ultrasound wave is generated, particles move to the node of the wave along the ultrasound force gradient. If the particles also undergo a sedimentation force, they aggregate at the equilibrium position, where these two forces are balanced. The equilibrium position, which is determined by the density and compressibility of a medium and particles, characterizes the particles. The local ultrasound energy, which is necessary for quantitative discussions, is evaluated by using a standard particle, the physical parameters of which are unambiguously determined; aluminum particles are used in the present study. The local ultrasound energy makes possible the determination of the compressibility of unknown materials. Nonporous particles of inorganic and polymeric materials, the particle sizes of which range from 3 to 100 microm, follow a derived model, suggesting that the local ultrasound energy and a derived model be valid. The proposed external field can be used for separation of particles having different acoustic natures.

Journal Article↗
PubMed2024

Major depletion of insulin sensitivity-associated taxa in the gut microbiome of persons living with HIV controlled by antiretroviral drugs.

BACKGROUND: Persons living with HIV (PWH) harbor an altered gut microbiome (higher abundance of Prevotella and lower abundance of Bacillota and Ruminococcus lineages) compared to non-infected individuals. Some of these alterations are linked to sexual preference and others to the HIV infection. The relationship between these lineages and metabolic alterations, often present in aging PWH, has been poorly investigated. METHODS: In this study, we compared fecal metagenomes of 25 antiretroviral-treatment (ART)-controlled PWH to three independent control groups of 25 non-infected matched individuals by means of univariate analyses and machine learning methods. Moreover, we used two external datasets to validate predictive models of PWH classification. Next, we searched for associations between clinical and biological metabolic parameters with taxonomic and functional microbiome profiles. Finally, we compare the gut microbiome in 7 PWH after a 17-week ART switch to raltegravir/maraviroc. RESULTS: Three major enterotypes (Prevotella, Bacteroides and Ruminococcaceae) were present in all groups. The first Prevotella enterotype was enriched in PWH, with several of characteristic lineages associated with poor metabolic profiles (low HDL and adiponectin, high insulin resistance (HOMA-IR)). Conversely butyrate-producing lineages were markedly depleted in PWH independently of sexual preference and were associated with a better metabolic profile (higher HDL and adiponectin and lower HOMA-IR). Accordingly with the worst metabolic status of PWH, butyrate production and amino-acid degradation modules were associated with high HDL and adiponectin and low HOMA-IR. Random Forest models trained to classify PWH vs. control on taxonomic abundances displayed high generalization performance on two external holdout datasets (ROC AUC of 80-82%). Finally, no significant alterations in microbiome composition were observed after switching to raltegravir/maraviroc. CONCLUSION: High resolution metagenomic analyses revealed major differences in the gut microbiome of ART-controlled PWH when compared with three independent matched cohorts of controls. The observed marked insulin resistance could result both from enrichment in Prevotella lineages, and from the depletion in species producing butyrate and involved into amino-acid degradation, which depletion is linked with the HIV infection.

Humans↗
PubMed2006

An accurate and interpretable bayesian classification model for prediction of HERG liability.

Drug-induced QT interval prolongation has been identified as a critical side-effect of non-cardiovascular therapeutic agents and has resulted in the withdrawal of many drugs from the market. As almost all cases of drug-induced QT prolongation can be traced to the blockade of a voltage-dependent potassium ion channel encoded by the hERG (the human ether-à-go-go-related gene), early identification of potential hERG channel blockers will decrease the risk of cardiotoxicity-induced attritions in the later and more expensive development stage. Presented herein is a naive Bayes classifier to categorize hERG blockers into active and inactive classes, by using a universal, generic molecular descriptor system.1 The naive Bayes classifier was built from a training set containing 1979 corporate compounds, and exhibited an ROC accuracy of 0.87. The model was validated on an external test set of 66 drugs, of which 58 were correctly classified. The cumulative probabilities reflected the confidence of prediction and were proven useful for the identification of hERG blockers. Relative performance was compared for two classifiers constructed from either an atom-type-based molecular descriptor or the long range functional class fingerprint descriptor FCFP_6. The combination of an atom-typing descriptor and the naive Bayes classification technique enables the interpretation of the resulting model, which offers extra information for the design of compounds free of undesirable hERG activity.

Bayes Theorem↗