Shesh N. Rai

The confounding effect of class size on the validity of object-oriented metrics

Much effort has been devoted to the development and empirical validation of object-oriented metrics. The empirical validations performed thus far would suggest that a core set of validated metrics is close to being identified. However, none of these studies allow for the potentially confounding effect of class size. We demonstrate a strong size confounding effect and question the results of previous object-oriented metrics validation studies. We first investigated whether there is a confounding effect of class size in validation studies of object-oriented metrics and show that, based on previous work, there is reason to believe that such an effect exists. We then describe a detailed empirical methodology for identifying those effects. Finally, we perform a study on a large C++ telecommunications framework to examine if size is really a confounder. This study considered the Chidamber and Kemerer metrics and a subset of the Lorenz and Kidd metrics. The dependent variable was the incidence of a fault attributable to a field failure (fault-proneness of a class). Our findings indicate that, before controlling for size, the results are very similar to previous studies. The metrics that are expected to be validated are indeed associated with fault-proneness.

Plasma miR-21: a potential diagnostic marker of colorectal cancer.

Objectives:The main objective of this study was to investigate the potential use of circulating microRNAs (miRNAs) as biomarkers of sporadic colorectal cancer (CRC). Background:CRC, a leading cause of death, is curable if detected early. There is an unmet need for an accurate, noninvasive biomarker of CRC. MiRNAs are non–protein-coding RNAs regulating gene expression that play a role in CRC development. Methods:Levels of 380 miRNAs were determined using microfluidic array technology (Applied Biosystems) in a “training” set of 30 CRC patients from whom cancer and adjacent normal tissue were collected. The 4 most dysregulated miRNAs (P < 0.05, false discovery rate (FDR): 10%) were then validated in a second blinded “test” set of 16 CRC patients from whom cancer and normal adjacent tissue had been collected. Validated tissue miRNAs were then evaluated in a plasma “test” set consisting of 30 CRC patients and 30 individuals without CRC. The most dysregulated tissue miRNAs were then validated in an independent new plasma test set consisting of 20 CRC patients with 20 age-, -, and race-matched subjects without CRC. Results:Nineteen of 380 miRNAs were dysregulated in CRC tissue in the tissue “training” set (P < 0.05, FDR: 10%). The 2 most upregulated (miR-31; miR-135b) and most downregulated (miR-1; miR-133a) miRNAs identified CRC in our “test” set with 100% sensitivity and 80% specificity. MiR-31 was more upregulated in stages III and IV compared with stages I and II (P < 0.05). In the “plasma” group, miR-21 differentiated CRC patients from controls with 90% specificity and sensitivity. Conclusions:Plasma miRNAs provide reliable and noninvasive markers for CRC. Plasma miR-21 warrants study in larger cohorts. It seems uniquely promising as a plasma biomarker for CRC.

Comparing case-based reasoning classifiers for predicting high risk software components

Abstract Case-based reasoning (CBR) has been proposed for predicting the risk class of software components. Risky components can be defined as those that are fault-prone, or those that require a large amount of effort to maintain. Thus far evaluative studies of CBR classifiers have been promising, showing that their predictive performance is as good as or better than other types of classifiers. However, a CBR classifier can be instantiated in different ways by varying its parameters, and it is not clear which combination of parameters provides the best performance. In this paper we evaluate the performance of a CBR classifier with different parameters, namely: (a) different distance measures, (b) different standardization techniques, (c) use or non-use of weights, and (d) the number of nearest neighbors to use for the prediction. In total, we compared 30 different CBR classifiers. The study was conducted with a data set from a large real-time system, and the objective was to predict the fault-proneness of its components. Our results indicate that there is no difference in prediction performance when using any combination of parameters. Based on these results, we recommend using a simple CBR classifier with Euclidean distance, z -score standardization, no weighting scheme, and selecting the single nearest neighbor for prediction. The advantage of such a classifier is its intuitive appeal to nonspecialists, and the fact that it performs as well as more complex classifiers.

Identifying mRNA, MicroRNA and Protein Profiles of Melanoma Exosomes

Background Exosomes are small membranous vesicles secreted into body fluids by multiple cell types, including tumor cells, and in various disease conditions. Tumor exosomes contain intact and functional mRNAs, small RNAs (including miRNAs), and proteins that can alter the cellular environment to favor tumor growth. Molecular profiling may increase our understanding of the role of exosomes in melanoma progression and may lead to discovery of useful biomarkers. Methodology/Principal Findings In the present study, we used mRNA array profiling to identify thousands of exosomal mRNAs associated with melanoma progression and metastasis. Similarly, miRNA array profiling identified specific miRNAs, such as hsa-miR-31, -185, and -34b, involved in melanoma invasion. We also used proteomic analysis and discovered differentially expressed melanoma exosomal proteins, including HAPLN1, GRP78, syntenin-1, annexin A1, and annexin A2. Importantly, normal melanocytes acquired invasion ability through molecules transported in melanoma cell-derived exosomes. Conclusions/Significance Our results indicate that melanoma-derived exosomes have unique gene expression signatures, miRNA and proteomics profiles compared to exosomes from normal melanocytes. To the best of our knowledge, this is the first in-depth screening of the whole transcriptome/miRNome/proteome expression in melanoma exosomes. These results provide a starting point for future more in-depth studies of tumor-derived melanoma exosomes, which will aid our understanding of melanoma biogenesis and new drug-targets that may be translated into clinical applications, or as non-invasive biomarkers for melanoma.

Symptoms of post-traumatic stress in children with cancer and their parents: Effects of informant and time from diagnosis

Post‐traumatic stress disorder (PTSD) has been put forth as a model for understanding the adjustment of children with cancer and their parents, but findings in the literature regarding the prevalence of post‐traumatic stress symptoms (PTSS) have been mixed. This study examined PTSS levels in both patients and parents as a function of time elapsed from diagnosis, and by use of parent versus child reports for assessing patient PTSS.

Nocturnal Awakenings, Sleep Environment Interruptions, and Fatigue in Hospitalized Children With Cancer

PURPOSE/OBJECTIVES To describe nocturnal awakenings and sleep environment interruptions experienced by children and adolescents hospitalized for two to four days to receive chemotherapy and to assess the relationships among nocturnal awakenings, sleep environment interruptions, sleep duration, and fatigue. DESIGN Longitudinal, descriptive design. SETTING St. Jude Childrens Research Hospital and Texas Childrens Cancer Center. SAMPLE 25 patients with solid tumors and 4 with acute myeloid leukemia. METHODS Actigraphy, fatigue instruments, sleep diary, room entry and exit checklists, and blood samples. MAIN RESEARCH VARIABLES Nocturnal awakenings, sleep environment interruptions, sleep duration, and fatigue. FINDINGS The number of nocturnal awakenings per night as measured by actigraphy ranged from 0-40. The number of room entries and exits by a staff member or parent was 3-22 times per eight-hour night shift. The number of nocturnal awakenings was related to fatigue by patient report; patients who experienced 20 or more awakenings had significantly higher fatigue scores than those with fewer awakenings. Nocturnal awakenings also were significantly associated with sleep duration by patient and parent report. CONCLUSIONS Hospitalized pediatric patients with cancer who experience more nocturnal awakenings are more fatigued and sleep longer. IMPLICATIONS FOR NURSING Nurses may be able to control some of the factors that contribute to nocturnal awakenings and sleep environment interruptions that affect fatigue and sleep duration in hospitalized pediatric patients with cancer.

Final Results of a Prospective Clinical Trial With VAMP and Low-Dose Involved-Field Radiation for Children With Low-Risk Hodgkin's Disease

PURPOSE To evaluate outcome and assess complications in children and adolescents with low-risk Hodgkins disease treated with vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) chemotherapy and low-dose, involved-field radiation therapy (IFRT). PATIENTS AND METHODS One hundred ten children with low-risk Hodgkins disease were treated with four cycles of VAMP and 15 Gy IFRT for those who achieved a complete response (CR) or 25.5 Gy for those with a partial response after two cycles of VAMP. RESULTS With median follow-up of 9.6 years (range, 1.7 to 15.0), 5- and 10-year overall survival were 99.1% and 96.1%, respectively, and 5-and 10-year event-free survival (EFS) were 92.7% and 89.4%. Factors contributing to 10-year EFS were: early CR (P = .02), absence of B symptoms (P = .01), lymphocyte predominant histologic subtype (P = .04), and less than three initial sites of disease (P = .02). Organ toxicity has been limited to correctable hypothyroidism in 42% of irradiated patients, and one case of cardiac dysfunction. Seventeen healthy babies have been born to 106 survivors. There have been two malignant tumors: one thyroid cancer within the radiation therapy field and one Ewings sarcoma outside the radiation therapy field. CONCLUSION Risk-adapted, combined-modality therapy using VAMP chemotherapy with radiation is effective and well tolerated. Pediatric patients with low-risk Hodgkins disease can be cured with therapy without an alkylating agent, bleomycin, etoposide, or high-dose, extended-field radiotherapy. Thus, these children are expected to retain normal fertility, organ function, and be at low risk of a second malignant tumor.

A plasma microRNA panel for detection of colorectal adenomas: a step toward more precise screening for colorectal cancer.

Objective:The main objective of this study was to investigate the potential use of circulating microRNAs (miRNAs) as biomarkers of colorectal (CR) adenomas. Background:Detection of precancerous lesions such as CR adenoma is a key to reduce CR cancer (CRC) mortality. There is a great need for accurate, noninvasive biomarkers for detection of CR adenoma and CRC. MiRNAs are non-protein-coding RNAs that regulate gene expression. Our prior work investigated the dysregulation of 5 plasma miRNAs in CRC patients. As intended, we undertook a more comprehensive plasma-miRNA screening study in patients with CR adenoma and CRC. Methods:We screened for 380 plasma-miRNAs using microfluidic array technology (Applied BioSystems) in a screening cohort of 12 healthy controls, 9 patients with CR adenomas, and 20 patients with CRC. A panel of the most dysregulated miRNAs (P < 0.05, False Discovery Rate: 5%) was then validated in a blinded cohort of 26 healthy controls, 16 patients with large adenomas, and 45 patients with CRC. Results:A panel of 8 plasma miRNAs (miR-532-3p, miR-331, miR-195, miR-17, miR-142-3p, miR-15b, miR-532, and miR-652) distinguished polyps from controls with high accuracy [area under curve (AUC) = 0.868 (95% confidence interval [CI]: 0.76–0.98)]. In addition, a panel of 3 plasma miRNAs (miR-431, miR-15b, and miR-139-3p) distinguished Stage IV CRC from controls with an [AUC = 0.896 (95% CI: 0.78–1.0)]. Receiver-operating-characteristic curves of miRNA panels for all CRC versus controls and polyps versus all CRC showed AUC values of 0.829 (95% CI: 0.73–0.93) and 0.856 (95% CI: 0.75–0.97), respectively. Conclusions:Plasma miRNAs are reliable, noninvasive, and inexpensive markers for CR adenomas. This miRNA panel warrants study in larger cohorts. Plasma-based assays could provide better screening compliance compared to fecal occult blood or endoscopic screening.

Quality of life as conveyed by pediatric patients with cancer

Quality-of-life instruments have provided important advances in measuring the quality of life of pediatric patients receiving treatment for cancer. However, the bases of these instruments have not included first-hand reports from the patients; thus, these instruments may be conceptually incomplete. We directly solicited from pediatric patients their perspectives regarding their quality of life during treatment for cancer. We conducted two pilot studies: 23 patients (aged 8–15 years) participated in the first, a cross-sectional study; and 13 patients (aged 10–18 years) participated in the second, a 2-year longitudinal study. Data were analyzed by using a semantic-content method, and the following six domains were recognized in data from both of the studies: symptoms, usual activities, social/family interactions, health status, mood, and the meaning of being ill. These domains were compared with those of seven established pediatric oncology quality-of-life instruments, none of which included all six of these domains; the domain most frequently missing was the meaning of being ill domain. Here we present a new definition of the quality of life of pediatric oncology patients that is based on six domains; this definition may ensure the completeness and sensitivity of these important instruments.

Differential microRNA expression tracks neoplastic progression in inflammatory bowel disease-associated colorectal cancer.

One of the most serious complications faced by patients with inflammatory bowel disease (IBD) is the potential development of colorectal cancer (CRC). There is a compelling need to enhance the accuracy of cancer screening of IBD patients. MicroRNAs (miRNAs) are small nonprotein‐coding RNAs that play important roles in CRC oncogenesis. In this study, we report differential miRNA expression in IBD patients with associated CRC from non‐neoplastic tissue to dysplasia and eventually cancer. In addition, we identify and examine the role of dysregulated miRNAs in the TP53 pathway. In our CD patients, six miRNAs were upregulated from non‐neoplastic tissue to dysplasia, but downregulated from dysplasia to cancer (miR‐122, miR‐181a, miR‐146b‐5p, let‐7e, miR‐17, miR‐143) (P < 0.001). Six differentially expressed miRNAs affected the TP53 pathway (miR‐122, miR‐214, miR‐372, miR‐15b, let‐7e, miR‐17) (P < 0.001). Using two human colon cancer cell lines (HT‐29 and HCT‐116), E2F1, an upstream regulator of TP53, was downregulated in both cell lines transfected with let‐7e (P < 0.05) as well as in HCT‐116 cells transfected with miR‐17 (P < 0.05). Additionally, cyclin G, a cell‐cycle regulator miR‐122 target was downregulated in both cell lines (P < 0.05). Unique differentially expressed miRNAs were observed in CD‐associated CRC progression. Six of these miRNAs had a tumorigenic effect on the TP53 pathway; the effect of three of which was studied using cell lines. Hum Mutat 33:551–560, 2012.