Hypothesis testing procedure for binary and multi-class F1 -scores in the paired design.

In modern medicine, medical tests are used for various purposes including diagnosis, disease screening, prognosis, and risk prediction. To quantify the performance of the binary medical test, we often use sensitivity, specificity, and negative and positive predictive values as measures. Additionally, the F 1 $$ {F}_1 $$ -score, which is defined as the harmonic mean of precision (positive predictive value) and recall (sensitivity), has come to be used in the medical field due to its favorable characteristics. The F 1 $$ {F}_1 $$ -score has been extended for multi-class classification, and two types of F 1 $$ {F}_1 $$ -scores have been proposed for multi-class classification: a micro-averaged F 1 $$ {F}_1 $$ -score and a macro-averaged F 1 $$ {F}_1 $$ -score. The micro-averaged F 1 $$ {F}_1 $$ -score pools per-sample classifications across classes and then calculates the overall F 1 $$ {F}_1 $$ -score, whereas the macro-averaged F 1 $$ {F}_1 $$ -score computes an arithmetic mean of the F 1 $$ {F}_1 $$ -scores for each class. Additionally, Sokolova and Lapalme 1 $$ {}^1 $$ gave an alternative definition of the macro-averaged F 1 $$ {F}_1 $$ -score as the harmonic mean of the arithmetic means of the precision and recall over classes. Although some statistical methods of inference for binary and multi-class F 1 $$ {F}_1 $$ -scores have been proposed, the methodology development of hypothesis testing procedure for them has not been fully progressing yet. Therefore, we aim to develop hypothesis testing procedure for comparing two F 1 $$ {F}_1 $$ -scores in paired study design based on the large sample multivariate central limit theorem.

The use of dried tube specimens of Plasmodium falciparum in an external quality assessment programme to evaluate health worker performance for malaria rapid diagnostic testing in healthcare centres in Togo.

BACKGROUND: The use of rapid diagnostic tests (RDTs) to diagnose malaria is common in sub-Saharan African laboratories, remote primary health facilities and in the community. Currently, there is a lack of reliable methods to ascertain health worker competency to accurately use RDTs in the testing and diagnosis of malaria. Dried tube specimens (DTS) have been shown to be a consistent and useful method for quality control of malaria RDTs; however, its application in National Quality Management programmes has been limited. METHODS: A Plasmodium falciparum strain was grown in culture and harvested to create DTS of varying parasite density (0, 100, 200, 500 and 1000 parasites/µL). Using the dried tube specimens as quality control material, a proficiency testing (PT) programme was carried out in 80 representative health centres in Togo. Health worker competency for performing malaria RDTs was assessed using five blinded DTS samples, and the DTS were tested in the same manner as a patient sample would be tested by multiple testers per health centre. RESULTS: All the DTS with 100 parasites/µl and 50% of DTS with 200 parasites/µl were classified as non-reactive during the pre-PT quality control step. Therefore, data from these parasite densities were not analysed as part of the PT dataset. PT scores across all 80 facilities and 235 testers was 100% for 0 parasites/µl, 63% for 500 parasites/µl and 93% for 1000 parasites/µl. Overall, 59% of the 80 healthcare centres that participated in the PT programme received a score of 80% or higher on a set of 0, 500 and 1000 parasites/ µl DTS samples. Sixty percent of health workers at these centres recorded correct test results for all three samples. CONCLUSIONS: The use of DTS for a malaria PT programme was the first of its kind ever conducted in Togo. The ease of use and stability of the DTS illustrates that this type of samples can be considered for the assessment of staff competency. The implementation of quality management systems, refresher training and expanded PT at remote testing facilities are essential elements to improve the quality of malaria diagnosis.

The DSM-5 introduction of the Social (Pragmatic) Communication Disorder as a new mental disorder: a philosophical review.

The latest edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) included the Social (Pragmatic) Communication Disorder (SPCD) as a new mental disorder characterized by deficits in pragmatic abilities. Although the introduction of SPCD in the psychiatry nosography depended on a variety of reasons-including bridging a nosological gap in the macro-category of Communication Disorders-in the last few years researchers have identified major issues in such revision. For instance, the symptomatology of SPCD is notably close to that of (some forms of) Autism Spectrum Disorder (ASD). This opens up the possibility that individuals with very similar symptoms can be diagnosed differently (with either ASD or SPCD) and receive different clinical treatments and social support. The aim of this paper is to review recent debates on SPCD, particularly as regards its independence from ASD. In the first part, we outline the major aspects of the DSM-5 nosological revision involving ASD and SPCD. In the second part, we focus on the validity and reliability of SPCD. First, we analyze literature on three potential validators of SPCD, i.e., etiology, response to treatment, and measurability. Then, we turn to reliability issues connected with the introduction of the grandfather clause and the use of the concepts of spectrum and threshold in the definition of ASD. In the conclusion, we evaluate whether SPCD could play any role in contemporary psychiatry other than that of an independent mental disorder and discuss the role that non-epistemic factors could play in the delineation of the future psychiatry nosography.

Personalized machine learning approach to predict candidemia in medical wards.

PURPOSE: Candidemia is a highly lethal infection; several scores have been developed to assist the diagnosis process and recently different models have been proposed. Aim of this work was to assess predictive performance of a Random Forest (RF) algorithm for early detection of candidemia in the internal medical wards (IMWs). METHODS: A set of 42 potential predictors was acquired in a sample of 295 patients (male: 142, age: 72 ± 15 years; candidemia: 157/295; bacteremia: 138/295). Using tenfold cross-validation, a RF algorithm was compared with a classic stepwise multivariable logistic regression model; discriminative performance was assessed by C-statistics, sensitivity and specificity, while calibration was evaluated by Hosmer-Lemeshow test. RESULTS: The best tuned RF algorithm demonstrated excellent discrimination (C-statistics = 0.874 ± 0.003, sensitivity = 84.24% ± 0.67%, specificity = 91% ± 2.63%) and calibration (Hosmer-Lemeshow statistics = 12.779 ± 1.369, p = 0.120), markedly greater than the ones guaranteed by the classic stepwise logistic regression (C-statistics = 0.829 ± 0.011, sensitivity = 80.21% ± 1.67%, specificity = 84.81% ± 2.68%; Hosmer-Lemeshow statistics = 38.182 ± 15.983, p < 0.001). In addition, RF suggests a major role of in-hospital antibiotic treatment with microbioma highly impacting antimicrobials (MHIA) that are found as a fundamental risk of candidemia, further enhanced by TPN. When in-hospital MHIA therapy is not performed, PICC is the dominant risk factor for candidemia, again enhanced by TPN. When PICC is not used and MHIA therapy is not performed, the risk of candidemia is minimum, slightly increased by in-hospital antibiotic therapy. CONCLUSION: RF accurately estimates the risk of candidemia in patients admitted to IMWs. Machine learning technique might help to identify patients at high risk of candidemia, reduce the delay in empirical treatment and improve appropriateness in antifungal prescription.

Multiple cross displacement amplification-a more applicable technique in detecting Pseudomonas aeruginosa of ventilator-associated pneumonia (VAP).

BACKGROUND: Early and rapid identification of Pseudomonas aeruginosa (P. aeruginosa) in patients with suspected ventilator-associated pneumonia (VAP) provides theoretical clinical advantages in therapeutic optimization strategies. METHODS: The P. aeruginosa-multiple cross displacement amplification (PA-MCDA) assay was conducted at an isothermal temperature during the amplification stage, and products were visually detected by color changes. The entire process was completed within 1 h. A total of 77 strains, including P. aeruginosa species and various other species of non-P. aeruginosa, were used to evaluate PA-MCDA assays. Bronchoalveolar lavage fluid (BALF) of suspected VAP patients was examined by the MCDA assay. RESULTS: The MCDA assay exhibited a 100% analytical specificity in detecting PA from all 77 strains, and the limit of detection was as low as 100 fg DNA per reaction. A temperature of 65 °C was recommended as standard during the amplification stage. The agreement between PA-MCDA and bacteria culture was 91.18% (κ = 0.787; p = 0.000) in the identification of P. aeruginosa in BALF from suspected VAP. The PA-MCDA assay showed values of 92.31%, 90.78%, 77.41%, and 97.18% for sensitivity, specificity, positive predictive value, and negative predictive value, respectively. PA-MCDA had a higher detective rate of P. aeruginosa than bacteria culture in patients with antipseudomonal therapy. CONCLUSIONS: The instrument-free platform of the MCDA assay makes it a simple, rapid, and applicable procedure for "on-site" diagnosis and point-of-care testing for the presence of P. aeruginosa without the need for specific bacterial culture.

Point of care aspergillus testing in intensive care patients.

BACKGROUND: Invasive pulmonary aspergillosis (IPA) is an increasingly recognized complication in intensive care unit (ICU) patients, especially those with influenza, cirrhosis, chronic obstructive pulmonary disease, and other diseases. The diagnosis can be challenging, especially in the ICU, where clinical symptoms as well as imaging are mostly nonspecific. Recently, Aspergillus lateral flow tests were developed to decrease the time to diagnosis of IPA. Several studies have shown promising results in bronchoalveolar lavage fluid (BALf) from hematology patients. We therefore evaluated a new lateral flow test for IPA in ICU patients. METHODS: Using left-over BALf from adult ICU patients in two university hospitals, we studied the performance of the Aspergillus galactomannan lateral flow assay (LFA) by IMMY (Norman, OK, USA). Patients were classified according to the 2008 EORTC-MSG definitions, the AspICU criteria, and the modified AspICU criteria, which incorporate galactomannan results. These internationally recognized consensus definitions for the diagnosis of IPA incorporate patient characteristics, microbiology and radiology. The LFA was read out visually and with a digital reader by researchers blinded to the final clinical diagnosis and IPA classification. RESULTS: We included 178 patients, of which 55 were classified as cases (6 cases of proven and 26 cases of probable IPA according to the EORTC-MSG definitions, and an additional 23 cases according to the modified AspICU criteria). Depending on the definitions used, the sensitivity of the LFA was 0.88-0.94, the specificity was 0.81, and the area under the ROC curve 0.90-0.94, indicating good overall test performance. CONCLUSIONS: In ICU patients, the LFA performed well on BALf and can be used as a rapid screening test while waiting for other microbiological results.

Prediabetes among HIV-infected individuals receiving antiretroviral therapy: prevalence, diagnostic tests, and associated factors.

BACKGROUND: Metabolic complications in human immunodeficiency virus (HIV)-infected individuals are common. Prediabetes represents a high risk for future diabetes development. This study aimed to determine the prevalence, diagnostic methods, and associated factors of prediabetes among HIV-infected individuals receiving antiretroviral therapy (ART). METHODS: A cross-sectional study was conducted among HIV-infected adults without a history of diabetes who were receiving ART. Fasting plasma glucose (FPG), 2-hour plasma glucose (2-h PG) after a 75-g oral glucose tolerance test, and hemoglobin A1c (HbA1c) were assessed. RESULTS: A total of 397 patients with a mean age of 47.0 ± 9.8 years and 55.7% male, were studied. All received ART with undetectable plasma viral load. The mean duration of ART was 9.6 ± 5.2 years, and the mean CD4 cell count was 554 ± 235 cells/mm3. Among the patients, 28 (7.1%) had first-diagnosed diabetes, and 133 (33.5%) patients had prediabetes. Glycemia estimation by FPG, 2-h PG, and HbA1c showed a prediabetes prevalence of 17.4%, 14.7%, and 12.5%, respectively. The kappa statistics for the agreement of FPG and 2-h PG, HbA1c and 2-h PG, and HbA1c and FPG were 0.317, 0.429, and 0.396, respectively. In multivariate analysis, hypertension [odds ratio (OR) 3.38; 95% confidence interval (CI), 1.16-9.91; p = 0.026), and triglycerides > 150 mg/dL (OR 2.11; 95% CI, 1.01-4.44; p = 0.047) were factors significantly associated with prediabetes. CONCLUSIONS: Prediabetes among HIV-infected individuals receiving ART is common. The agreements of glycemia estimation methods are minimal to weak. HbA1c may underestimate prediabetes prevalence. Using FPG together with HbA1c increases the detection rate to approximately three-quarters of prediabetes patients. HIV-infected individuals who had hypertension and hypertriglyceridemia should be regularly assessed for prediabetes. Trial registration ClinicalTrial.gov, NCT03545217. Registered 1 June 2018-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03545217.

A comprehensive and comparative review of optimal cut-points selection methods for diseases with multiple ordinal stages.

Cut-points selection is a key topic in the field of diagnostic studies. For binary classification, there exist several well-developed methods, some of which have been extended to three-class settings and beyond. This paper focuses on optimal cut-points selection methods for diseases with multiple ordinal stages. The purpose of this paper is two-fold: 1) to propose three new cut-points selection methods; and 2) to present a comprehensive simulation study to assess and compare the performance of all the available methods. Two real data sets, one from ovarian cancer and the other from pancreatic cancer, are analyzed.

The association between palliative care team consultation and hospital costs for patients with advanced cancer: An observational study in 12 Dutch hospitals.

BACKGROUND: Early palliative care team consultation has been shown to reduce costs of hospital care. The objective of this study was to investigate the association between palliative care team (PCT) consultation and the content and costs of hospital care in patients with advanced cancer. MATERIAL AND METHODS: A prospective, observational study was conducted in 12 Dutch hospitals. Patients with advanced cancer and an estimated life expectancy of less than 1 year were included. We compared hospital care during 3 months of follow-up for patients with and without PCT involvement. Propensity score matching was used to estimate the effect of PCTs on costs of hospital care. Additionally, gamma regression models were estimated to assess predictors of hospital costs. RESULTS: We included 535 patients of whom 126 received PCT consultation. Patients with PCT had a worse life expectancy (life expectancy <3 months: 62% vs. 31%, p < .01) and performance status (p < .01, e.g., WHO status higher than 2:54% vs. 28%) and more often had no more options for anti-tumour therapy (57% vs. 30%, p < .01). Hospital length of stay, use of most diagnostic procedures, medication and other therapeutic interventions were similar. The total mean hospital costs were €8,393 for patients with and €8,631 for patients without PCT consultation. Analyses using propensity scores to control for observed confounding showed no significant difference in hospital costs. CONCLUSIONS: PCT consultation for patients with cancer in Dutch hospitals often occurs late in the patients' disease trajectories, which might explain why we found no effect of PCT consultation on costs of hospital care. Earlier consultation could be beneficial to patients and reduce costs of care.

Which procedures are performed by general internists practicing primary care in Germany? - a cross-sectional study.

BACKGROUND: Due to differences of residency training programs' emphases - inpatient vs office-based - internal medicine and family medicine residents consistently reported differences in preparedness to care for common adult conditions. Study's aim was to add knowledge about procedures that a) are performed by general internists working in primary care and b) should be learned during residency in general internists' appraisal. METHODS: A cross-sectional postal survey was carried out by using a questionnaire that comprised 90 procedures relevant in primary care. Each procedure implied the two questions "Do you perform this procedure in your own practice?" and "How important do you think it is to learn this procedure during residency?" The final questionnaire was sent to 1002 general internists working in primary care in Germany in May 2015. Data analysis was performed using SPSS Version 24.0 (SPSS inc., IBM). Next to descriptive statistics subgroup analyses were performed using cross tabulation and Chi-square tests for evaluation of differences in the performance of most frequently performed procedures in urban or rural areas as well as by male or female physicians. RESULTS: Twenty-eight percent of sent questionnaires (276/1002) could be included in analysis. Mean age of participants was 52 years with 13 years of practice experience; 40% were female. Twenty-nine (32%) of 90 given procedures were performed by at least half of the participants, foremost technical diagnostics, punctures, procedures of the integument and resuscitation. After Bonferroni correction, five of those procedures were performed by more male than female physicians and two procedures by more physicians working in a rural practice than physicians practicing in an urban location. Moreover, 46 (51%) procedures were assessed as important to learn during residency by at least 50% of participants. CONCLUSIONS: General internists working in German primary care perform a narrow scope of procedures offered by primary care physicians. In order to provide best ambulatory care for patients, residency training programs must ensure training in procedures that are necessary for providing high quality care. Therefore, a consensus aligned with patients' and health-systems' needs on procedures required for working as a general internist in primary care is necessary.

Pathologists should probably forget about kappa. Percent agreement, diagnostic specificity and related metrics provide more clinically applicable measures of interobserver variability.

Kappa statistics have been widely used in the pathology literature to compare interobserver diagnostic variability (IOV) among different pathologists but there has been limited discussion about the clinical significance of kappa scores. Five representative and recent pathology papers were queried using clinically relevant specific questions to learn how IOV was evaluated and how the clinical applicability of results was interpreted. The papers supported our anecdotal impression that pathologists usually assess IOV using Cohen's or Fleiss' kappa statistics and interpret the results using some variation of the scale proposed by Landis and Koch. The papers did not cite or propose specific guidelines to comment on the clinical applicability of results. The solutions proposed to decrease IOV included the development of better diagnostic criteria and additional educational efforts, but the possibility that the entities themselves represented a continuum of morphologic findings rather than distinct diagnostic categories was not considered in any of the studies. A dataset from a previous study of IOV reported by Thunnissen et al. was recalculated to estimate percent agreement among 19 international lung pathologists for the diagnosis of 74 challenging lung neuroendocrine neoplasms. Kappa scores and diagnostic sensitivity, specificity, positive and negative predictive values were calculated using the majority consensus diagnosis for each case as the gold reference diagnosis for that case. Diagnostic specificity estimates among multiple pathologists were > 90%, although kappa scores were considerably more variable. We explain why kappa scores are of limited clinical applicability in pathology and propose the use of positive and negative percent agreement and diagnostic specificity against a gold reference diagnosis to evaluate IOV among two and multiple raters, respectively.

A retrospective review of multiple findings in diagnostic exome sequencing: half are distinct and half are overlapping diagnoses.

PURPOSE: We evaluated clinical and genetic features enriched in patients with multiple Mendelian conditions to determine which patients are more likely to have multiple potentially relevant genetic findings (MPRF). METHODS: Results of the first 7698 patients who underwent exome sequencing at Ambry Genetics were reviewed. Clinical and genetic features were examined and degree of phenotypic overlap between the genetic diagnoses was evaluated. RESULTS: Among patients referred for exome sequencing, 2% had MPRF. MPRF were more common in patients from consanguineous families and patients with greater clinical complexity. The difference in average number of organ systems affected is small: 4.3 (multiple findings) vs. 3.9 (single finding) and may not be distinguished in clinic. CONCLUSION: Patients with multiple genetic diagnoses had a slightly higher number of organ systems affected than patients with single genetic diagnoses, largely because the comorbid conditions affected overlapping organ systems. Exome testing may be beneficial for all cases with multiple organ systems affected. The identification of multiple relevant genetic findings in 2% of exome patients highlights the utility of a comprehensive molecular workup and updated interpretation of existing genomic data; a single definitive molecular diagnosis from analysis of a limited number of genes may not be the end of a diagnostic odyssey.

A new semiparametric transformation approach to disease diagnosis with multiple biomarkers.

When multiple biomarkers are available for disease diagnosis, it is desirable to efficiently combine them to form a single index. Making use of the Neyman-Pearson paradigm, we propose a new combination/transformation approach to disease diagnosis that efficiently combines multiple biomarkers. The proposed method does not require that the biomarkers be jointly normally distributed or the covariance matrices for the diseased and the nondiseased are nondifferential. An R package is developed to implement the proposed method. Simulations and two real data examples demonstrate advantages of the new method over existing ones.

Identifying Which Place Characteristics are Associated with the Odds of Recent HIV Testing in a Large Sample of People Who Inject Drugs in 19 US Metropolitan Areas.

This exploratory analysis investigates relationships of place characteristics to HIV testing among people who inject drugs (PWID). We used CDC's 2012 National HIV Behavioral Surveillance (NHBS) data among PWID from 19 US metropolitan statistical areas (MSAs); we restricted the analytic sample to PWID self-reporting being HIV negative (N = 7477). Administrative data were analyzed to describe the 1. Sociodemographic Composition; 2. Economic disadvantage; 3. Healthcare Service/Law enforcement; and 4. HIV burden of the ZIP codes, counties, and MSAs where PWID lived. Multilevel models tested associations of place characteristics with HIV testing. Fifty-eight percent of PWID reported past-year testing. MSA-level per capita correctional expenditures were positively associated with recent HIV testing among black PWID, but not white PWID. Higher MSA-level household income and imbalanced sex ratios (more women than men) in the MSA were associated with higher odds of testing. HIV screening for PWID is suboptimal (58%) and needs improvement. Identifying place characteristics associated with testing among PWID can strengthen service allocation and interventions in areas of need to increase access to HIV testing.

Risk of Ovarian Malignancy Algorithm versus Risk Malignancy Index-I for Preoperative Assessment of Adnexal Masses: A Systematic Review and Meta-Analysis.

PURPOSE: To perform a systematic review and meta-analysis of studies comparing the diagnostic accuracy of Risk of Ovarian Malignancy Algorithm (ROMA) and risk of malignancy index (RMI) for detecting ovarian cancer. METHODS: A systematic review and meta-analysis was performed according to PRISMA statement. A search for studies evaluating the diagnostic performance of ROMA and RMI-I indices for detecting ovarian malignancy from January 2010 to October 2018 was performed in the PubMed/MEDLINE and Web of Science databases. The quality of the studies was evaluated by the Quality Assessment of Diagnostic Accuracy Studies 2. RESULTS: Sixty-six citations were identified. After exclusions, 8 papers comprising 2,662 women (1,319 premenopausal and 1,343 postmenopausal) were ultimately included. The mean prevalence of ovarian malignancy was 29.0% in premenopausal women and 51.0% in postmenopausal women. High risk of bias for patient selection was observed for most studies. ROMA and RMI-I had a similar diagnostic performance in postmenopausal women (pooled sensitivity [87 vs. 77%] and specificity [75 vs. 85%], respectively. p = 0.29). In premenopausal women, RMI-I showed better specificity than ROMA (89 vs. 78%, p = 0.022) with similar sensitivity (73 vs. 80%, p= 0.27). Significant heterogeneity was found for sensitivity and specificity in comparisons of both groups. CONCLUSIONS: ROMA and RMI-I have similar diagnostic performance for detecting ovarian cancer in women presenting with an adnexal mass. However, RMI-I showed a higher specificity than ROMA in premenopausal women. Notwithstanding, as the risk of bias is high in most studies, our results should be interpreted with caution.

Challenges, consequences, and lessons for way-outs to emergencies at hospitals: a systematic review study.

BACKGROUND: Emergency Department (ED) overcrowding adversely affects patients' health, accessibility, and quality of healthcare systems for communities. Several studies have addressed this issue. This study aimed to conduct a systematic review study concerning challenges, lessons and way outs of clinical emergencies at hospitals. METHODS: Original research articles on crowding of emergencies at hospitals published from 1st January 2007, and 1st August 2018 were utilized. Relevant studies from the PubMed and EMBASE databases were assessed using suitable keywords. Two reviewers independently screened the titles, abstracts and the methodological validity of the records using data extraction format before their inclusion in the final review. Discussions with the senior faculty member were used to resolve any disagreements among the reviewers during the assessment phase. RESULTS: Out of the total 117 articles in the final record, we excluded 11 of them because of poor quality. Thus, this systematic review synthesized the reports of 106 original articles. Overall 14, 55 and 29 of the reviewed refer to causes, effects, and solutions of ED crowding, respectively. The review also included four articles on both causes and effects and another four on causes and solutions. Multiple individual patients and healthcare system related challenges, experiences and responses to crowding and its consequences are comprehensively synthesized. CONCLUSION: ED overcrowding is a multi-facet issue which affects by patient-related factors and emergency service delivery. Crowding of the EDs adversely affected individual patients, healthcare delivery systems and communities. The identified issues concern organizational managers, leadership, and operational level actions to reduce crowding and improve emergency healthcare outcomes efficiently.

Detecting Secular Trends in Clinical Treatment through Temporal Analysis.

Medical treatments change over time for multiple reasons, including introduction of new treatments, availability of new scientific evidence, change in institutional guidelines, and market efforts by pharmaceutical and medical device companies. Monitoring and analyzing these secular trends will also inform the evaluation of evidence based practice as well as outcome research. Using a large national clinical dataset from the United States Veterans Health Administration (VHA), we measured the change in prevalence of all diseases, medications, and procedures by year from 2001 to 2014. To assess statistical significance, we used a generalized linear model. Among the large number of changes that were observed, multiple significant changes were related to diabetes mellitus type II (DM2). Prevalence of DM2 in the VHA increased after 2001 but plateaued by 2008; blood sugar testing by glycosylated hemoglobin increased consistently while glucose testing decreased; and the trend of insulin and metformin use was consistent with the trend in DM2 prevalence, while glyburide and rosiglitazone use dropped sharply.

A Robust Approach for Identification of Cancer Biomarkers and Candidate Drugs.

Background and objectives: Identification of cancer biomarkers that are differentially expressed (DE) between two biological conditions is an important task in many microarray studies. There exist several methods in the literature in this regards and most of these methods designed especially for unpaired samples, those are not suitable for paired samples. Furthermore, the traditional methods use p-values or fold change (FC) values to detect the DE genes. However, sometimes, p-value based results do not comply with FC based results due to the smaller pooled variance of gene expressions, which occurs when variance of each individual condition becomes smaller. There are some methods that combine both p-values and FC values to solve this problem. But, those methods also show weak performance for small sample cases in the presence of outlying expressions. To overcome this problem, in this paper, an attempt is made to propose a hybrid robust SAM-FC approach by combining rank of FC values and rank of p-values computed by SAM statistic using minimum ß-divergence method, which is designed for paired samples. Materials and Methods: The proposed method introduces a weight function known as ß-weight function. This weight function produces larger weights corresponding to usual and smaller weights for unusual expressions. The ß-weight function plays the significant role on the performance of the proposed method. The proposed method uses ß-weight function as a measure of outlier detection by setting ß = 0.2. We unify both classical and robust estimates using ß-weight function, such that maximum likelihood estimators (MLEs) are used in absence of outliers and minimum ß-divergence estimators are used in presence of outliers to obtain reasonable p-values and FC values in the proposed method. Results: We examined the performance of proposed method in a comparison of some popular methods (t-test, SAM, LIMMA, Wilcoxon, WAD, RP, and FCROS) using both simulated and real gene expression profiles for both small and large sample cases. From the simulation and a real spike in data analysis results, we observed that the proposed method outperforms other methods for small sample cases in the presence of outliers and it keeps almost equal performance with other robust methods (Wilcoxon, RP, and FCROS) otherwise. From the head and neck cancer (HNC) gene expression dataset, the proposed method identified two additional genes (CYP3A4 and NOVA1) that are significantly enriched in linoleic acid metabolism, drug metabolism, steroid hormone biosynthesis and metabolic pathways. The survival analysis through Kaplan-Meier curve revealed that combined effect of these two genes has prognostic capability and they might be promising biomarker of HNC. Moreover, we retrieved the 12 candidate drugs based on gene interaction from glad4u and drug bank literature based gene associations. Conclusions: Using pathway analysis, disease association study, protein-protein interactions and survival analysis we found that our proposed two additional genes might be involved in the critical pathways of cancer. Furthermore, the identified drugs showed statistical significance which indicates that proteins associated with these genes might be therapeutic target in cancer.

Validity of an online 24-h recall tool (myfood24) for dietary assessment in population studies: comparison with biomarkers and standard interviews.

BACKGROUND: Online dietary assessment tools can reduce administrative costs and facilitate repeated dietary assessment during follow-up in large-scale studies. However, information on bias due to measurement error of such tools is limited. We developed an online 24-h recall (myfood24) and compared its performance with a traditional interviewer-administered multiple-pass 24-h recall, assessing both against biomarkers. METHODS: Metabolically stable adults were recruited and completed the new online dietary recall, an interviewer-based multiple pass recall and a suite of reference measures. Longer-term dietary intake was estimated from up to 3 × 24-h recalls taken 2 weeks apart. Estimated intakes of protein, potassium and sodium were compared with urinary biomarker concentrations. Estimated total sugar intake was compared with a predictive biomarker and estimated energy intake compared with energy expenditure measured by accelerometry and calorimetry. Nutrient intakes were also compared to those derived from an interviewer-administered multiple-pass 24-h recall. RESULTS: Biomarker samples were received from 212 participants on at least one occasion. Both self-reported dietary assessment tools led to attenuation compared to biomarkers. The online tools resulted in attenuation factors of around 0.2-0.3 and partial correlation coefficients, reflecting ranking intakes, of approximately 0.3-0.4. This was broadly similar to the more administratively burdensome interviewer-based tool. Other nutrient estimates derived from myfood24 were around 10-20% lower than those from the interviewer-based tool, with wide limits of agreement. Intraclass correlation coefficients were approximately 0.4-0.5, indicating consistent moderate agreement. CONCLUSIONS: Our findings show that, whilst results from both measures of self-reported diet are attenuated compared to biomarker measures, the myfood24 online 24-h recall is comparable to the more time-consuming and costly interviewer-based 24-h recall across a range of measures.

Simultaneous inference for factorial multireader diagnostic trials.

We study inference methods for the analysis of multireader diagnostic trials. In these studies, data are usually collected in terms of a factorial design involving the factors Modality and Reader. Furthermore, repeated measures appear in a natural way since the same patient is observed under different modalities by several readers and the repeated measures may have a quite involved dependency structure. The hypotheses are formulated in terms of the areas under the ROC curves. Currently, only global testing procedures exist for the analysis of such data. We derive rank-based multiple contrast test procedures and simultaneous confidence intervals which take the correlation between the test statistics into account. The procedures allow for testing arbitrary multiple hypotheses. Extensive simulation studies show that the new approaches control the nominal type 1 error rate very satisfactorily. A real data set illustrates the application of the proposed methods.