Highest Combined Score Research Articles

Novel stratification of the recurrence risk following surgical extirpation of clear cell renal cell carcinoma using tissue biomarkers in the mammalian target of rapamycin pathway.

4581 Background: Aberrant activation of the mammalian target of rapamycin (mTOR) pathway promotes invasiveness and metastatic potential in a variety of malignancies. The aim of the present study was to evaluate the association of altered expression of mTOR pathway components with recurrence outcome in non-metastatic clear cell renal cell carcinoma (ccRCC) patients. Methods: Immunohistochemistry for phos-S6, phos-mTOR, mTOR, phos-AKT, HIF-1α, RAPTOR, PTEN, PI3K, and phos-4EBP1 was performed on tissue microarrays of patients treated for non-metastatic kidney cancer between 1997-2010. Patients were defined as having a low (<) or high risk (≥) of nomogram predicted recurrence (2001 MSKCC RCC post-op) using an 8% cutoff. The relationship between individual marker expression, as well as combined marker score (low, intermediate and high defined as ≤ 3, 4-5, >5 altered biomarkers; respectively) with the actual and predicted relapse rates was assessed. Results: The study included 419 non- metastatic ccRCC patients (pT1-T2 79.5%, pT3-T4 20.5%, Fuhrman nuclear grade 1-2 in 69%, 3-4 in 31%). 219 and 200 patients had low (<8%) and high (≥8%) nomogram-predicted 5-year risk of recurrence respectively. With a median follow-up of 2.2 years, recurrences were detected in 5 (2.3%) of the predicted low risk and 30 (15%) of the predicted high risk patients. mTOR pathway biomarker profiles were not predictive for patients at low predicted risk of recurrences. For patients at high predicted risk of recurrence, low, intermediate and high combined marker scores were found in 84 (42%), 79 (39.5%), and 37 (18.5%), respectively. The actual rates of recurrence were noted for 8.3% of low, 13.9% of intermediate and 32.4% of high combined marker score in a statistically significant distribution (p=0.027). Conclusions: The cumulative number of aberrantly expressed mTOR biomarkers correlates with a higher rate of recurrence. The combined marker score may help further stratify patients with high nomogram predicted risk of recurrence. Our data supports prospective evaluation of these biomarkers to augment current clinico-pathologic predictors of outcomes in ccRCC.

Novel stratification of the recurrence risk following surgical extirpation of clear cell renal cell carcinoma using tissue biomarkers in the mammalian target of rapamycin pathway.

372 Background: Aberrant activation of the mammalian target of rapamycin (mTOR) pathway promotes invasiveness and metastatic potential in a variety of malignancies. The aim of the present study was to evaluate the association of altered expression of mTOR pathway components with recurrence outcome in non-metastatic clear cell renal cell carcinoma (ccRCC) patients. Methods: Immunohistochemistry for phos-S6, phos-mTOR, mTOR, phos-AKT, HIF-1α, RAPTOR, PTEN, PI3K, and phos-4EBP1 was performed on tissue microarrays of patients treated for non-metastatic kidney cancer between 1997-2010. Patients were defined as having a low (<) or high risk (≥) of nomogram predicted recurrence (2001 MSKCC RCC post-op) using an 8% cutoff. The relationship between individual marker expression, as well as combined marker score (low, intermediate and high defined as ≤ 3, 4-5, >5 altered biomarkers; respectively) with the actual and predicted relapse rates was assessed. Results: The study included 419 non-metastatic ccRCC patients (pT1-T2 79.5%, pT3-T4 20.5%, Fuhrman nuclear grade 1-2 in 69%, 3-4 in 31%). 219 and 200 patients had low (<8%) and high (≥8%) nomogram-predicted 5-year risk of recurrence respectively. With a median follow-up of 2.2 years, recurrences were detected in 5 (2.3%) of the predicted low risk and 30 (15%) of the predicted high risk patients. mTOR pathway biomarker profiles were not predictive for patients at low predicted risk of recurrences. For patients at high predicted risk of recurrence, low, intermediate and high combined marker scores were found in 84 (42%), 79 (39.5%), and 37 (18.5%), respectively. The actual rates of recurrence were noted for 8.3% of low, 13.9% of intermediate and 32.4% of high combined marker score in a statistically significant distribution (p=0.027). Conclusions: The cumulative number of aberrantly expressed mTOR biomarkers correlates with a higher rate of recurrence. The combined marker score may help further stratify patients with high nomogram predicted risk of recurrence. Our data supports prospective evaluation of these biomarkers to augment current clinico-pathologic predictors of outcomes in ccRCC.

Optimal technology selection considering input levels of resource

PurposeThe purpose of this paper is to propose an optimal technology selection (OTS) method considering technology alternatives' required input levels of resource, to help companies select an optimal technology.Design/methodology/approachThe proposed method clustered technology alternatives according to their required input levels of resource. After that, in each cluster, the proposed method used data envelopment analysis‐assurance region (DEA‐AR) and analytic hierarchy process (AHP) rating method to evaluate the efficiencies and priorities of the technology alternatives, respectively. Finally, combined scores of the technology alternatives were calculated. A company can choose a proper technology cluster, and then select the technology alternative with the highest combined score within the selected cluster as the optimal technology.FindingsThe results showed that the OTS method cannot only select suitable technology which accords with a company's actual input capabilities, but also provide a more accurate selection result.Originality/valueTraditionally, technologies are evaluated without considering the technologies' required input levels, and simply ranked for selection. However, there are differences between a company's actual resource levels and a selected technology's required input levels of resource. This study proposes an integrated method to evaluate technology systematically and provides a more reasonable selection process for selecting optimal technology.

CASOS: a subspace method for anomaly detection in high dimensional astronomical databases

AbstractWe develop a novel algorithm for detecting anomalies. Our method has been developed to suit the challenging task of detecting anomalous sources in cross‐matched astronomical survey data. Our algorithm computes anomaly scores in lower‐dimensional subspaces of the data. By subspaces we mean, in this work, subsets of the original data variables. Our technique presents several advantages over existing methods: it can work directly on data with missing values; it addresses some of the problems posed by high‐dimensional data spaces; it is less susceptible to a masking effect from irrelevant features; it can be easily adapted to suit specific needs and it allows an easier interpretation of why a given object has a high combined anomaly score. One drawback of our method is that it cannot detect outliers that are only apparent in high‐dimensional spaces. Anomaly scores are computed using a nearest neighbor (NN) technique, but the algorithm works with any other method computing numerical anomaly scores. We demonstrate the properties of our algorithm and evaluate its performance on both simulated and real datasets. We show that it is capable of outperforming state‐of‐the‐art, full‐dimensional approaches in some situations. © 2013 Wiley Periodicals, Inc. Statistical Analysis and Data Mining 6: 53–72, 2013

A 12-Gene Expression Signature Is Associated with Aggressive Histological in Prostate Cancer: SEC14L1 and TCEB1 Genes Are Potential Markers of Progression

The main challenge for clinical management of prostate cancer is to distinguish tumors that will progress faster and will show a higher tendency to recur from the more indolent ones. We have compared expression profiles of 18 prostate cancer samples (seven with a Gleason score of 6, eight with a Gleason score of 7, and three with a Gleason score of ≥8) and five nonneoplastic prostate samples, using the Affymetrix Human Array GeneChip Exon 1.0 ST. Microarray analysis revealed 99 genes showing statistically significant differences among tumors with Gleason scores of 6, 7, and ≥8. In addition, mRNA expression of 29 selected genes was analyzed by real-time quantitative RT-PCR with microfluidic cards in an extended series of 30 prostate tumors. Of the 29 genes, 18 (62%) were independently confirmed in the extended series by quantitative RT-PCR: 14 were up-regulated and 4 were down-regulated in tumors with a higher Gleason score. Twelve of these genes were differentially expressed in tumors with a Gleason score of 6 to 7 versus ≥8. Finally, IHC validation of the protein levels of two genes from the 12-gene signature (SEC14L1 and TCEB1) showed strong protein expression levels of both genes, which were statistically associated with a high combined Gleason score, advanced stage, and prostate-specific antigen progression. This set of genes may contribute to a better understanding of the molecular basis of prostate cancer. TCEB1 and SELC14L1 are good candidate markers for predicting prognosis and progression of prostate cancer.

Prognosis of breast cancer is associated with one-carbon metabolism related nutrients among Korean women

BackgroundThe 5-year survival rate for breast cancer among Korean women has increased steadily; however, breast cancer remains the leading cause of cancer mortality among women. One-carbon metabolism, which requires an adequate supply of methyl group donors and B vitamins, may affect the prognosis of breast cancer. This aim of this study was to investigate the associations of dietary intake of vitamin B2, vitamin B6 and folate before diagnosis on the prognosis of breast cancer.MethodsWe assessed the dietary intake using a food frequency questionnaire with 980 women who were newly diagnosed and histopathologically confirmed to have primary breast cancer from hospitals in Korea, and 141 disease progression events occurred. Cox’s proportional hazard regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (95% CI) adjusting for age, education, recruitment sites, TNM stage, hormone status, nuclear grade and total calorie.ResultsThere was no significant association between any one-carbon metabolism related nutrients (vitamin B2, B6 and folate) and the progression of breast cancer overall. However, one-carbon metabolism related nutrients were associated with disease progression in breast cancer patients stratified by subtypes. In ER + and/or PR + breast cancers, no association was observed; however, in ER–/PR– breast cancers, a high intake of vitamin B2 and folate statistically elevated the HR of breast cancer progression (HR = 2.28; 95% CI, 1.20-4.35, HR = 1.84; 95% CI, 1.02-3.32, respectively) compared to a low intake. This positive association between the ER/PR status and progression of the disease was profound when the nutrient intakes were categorized in a combined score (Pinteraction = 0.018). In ER–/PR– breast cancers, high combined scores were associated with a significantly poor DFS compared to those belonging to the low score group (HR = 3.84; 95% CI, 1.70-8.71).ConclusionsIn conclusion, our results suggest that one-carbon related nutrients have a role in the prognosis of breast cancer depending on the ER/PR status.

DCLK1 immunoreactivity in colorectal neoplasia

IntroductionMicrotubule-associated doublecortin and CaM kinase-like-1 (DCLK1) is a novel candidate marker for intestinal stem cells. The aim of our study was to assess DCLK1 immunoreactivity in colorectal carcinogenesis and its correlation with prognosis.MethodsDCLK1 immunostaining was performed in colorectal tissue from 71 patients, including 18 adenomatous polyps, 40 primary adenocarcinomas, and 14 metastatic lesions. Each case was evaluated by a combined scoring method based on the intensity of staining (score 0–3) and the percentage of tissue staining positive (score 0–3). Immunoexpression for DCLK1 was considered as positive when the combined score was 2–6 and negative with a score of 0–1.ResultsOverall, 14/18 (78%) of polyps, 30/40 (75%) of primary adenocarcinomas, and 7/14 (50%) of distant metastases were positive for DCLK1. In adenomatous polyps and primary cancer there was no association between DCLK1 staining score and tumor pathology. However, after curative colorectal cancer resection, patients whose tumor had a high (≥5) combined staining score had increased cancer-specific mortality compared to patients with low (0–4) staining score (hazard ratio 5.89; 95% confidence interval: 1.22–28.47; P = 0.027).ConclusionWe found that DCLK1 is frequently expressed in colorectal neoplasia and may be associated with poor prognosis. Further studies are necessary to validate the use of DCLK1 as a prognostic marker.

Predictors of Anatomical Patency Following Primary Endonasal Dacryocystorhinostomy: A Pilot Study

Purpose: To identify factors influencing early anatomical patency following primary endonasal dacryocystorhinostomy (DCR) for nasolacrimal obstruction.Methods: A prospective study of 50 patients who underwent primary endonasal DCR for nasolacrimal obstruction was undertaken. Age, gender, dacryocystitis, endonasal access, clearance (bony clearance superiorly from the common canaliculus after bone removal), mobility (mobility of the flaps created from the lacrimal sac once opened), marsupialization (degree of reflection of the lacrimal sac following surgical opening) and a combined score (incorporating clearance, mobility and marsupialization) were examined. Outcomes were measured 10 weeks postoperatively by assessing anatomical patency via probe and syringe and modified functional endoscopic dye test.Results: Using the Kendall’s tau-beta test, there was a significant relationship between greater mobility and better outcome (p<.03) and greater marsupialization and better outcome (p=.03). A higher combined score (incorporating mobility, marsupialization and bony clearance) was also related to better outcome (p<.02). There was no significant relationship between outcome and age, gender, dacryocystitis, endonasal access or bony clearance. Overall, 47 patients (94%) had complete or partial patency at 10 weeks and 3 patients (6%) had complete nasolacrimal obstruction at 10 weeks.Conclusions: Greater flap mobility and greater lacrimal sac marsupialization in endonasal DCR are associated with better rates of early anatomical patency. A novel scoring system incorporating mobility, marsupialization and bony clearance also showed a significant relationship to early outcome, with higher scores being associated with better outcomes. These results may enable greater understanding of the perioperative features associated with better outcomes in endonasal DCR.

Efficient top- k aggregation of ranked inputs

A top- k query combines different rankings of the same set of objects and returns the k objects with the highest combined score according to an aggregate function. We bring to light some key observations, which impose two phases that any top- k algorithm, based on sorted accesses, should go through. Based on them, we propose a new algorithm, which is designed to minimize the number of object accesses, the computational cost, and the memory requirements of top- k search with monotone aggregate functions. We provide an analysis for its cost and show that it is always no worse than the baseline “no random accesses” algorithm in terms of computations, accesses, and memory required. As a side contribution, we perform a space analysis, which indicates the memory requirements of top- k algorithms that only perform sorted accesses. For the case, where the required space exceeds the available memory, we propose disk-based variants of our algorithm. We propose and optimize a multiway top- k join operator, with certain advantages over evaluation trees of binary top- k join operators. Finally, we define and study the computation of top- k cubes and the implementation of roll-up and drill-down operations in such cubes. Extensive experiments with synthetic and real data show that, compared to previous techniques, our method accesses fewer objects, while being orders of magnitude faster.

Association of Anxiety and Depression with Reported Disease Severity in Patients Undergoing Evaluation for Chronic Rhinosinusitis

We sought to determine the impact of psychiatric comorbidity on symptom density and resource utilization in chronic rhinosinusitis (CRS). A prospective cohort of patients who sought evaluation of CRS was studied with the Rhinosinusitis Symptom Inventory and the Hospital Anxiety and Depression Scale. Data concerning symptom scores, symptom domains, and psychiatric comorbidity were analyzed to determine the interactions among psychiatric comorbidity, symptom reporting, and resource utilization in CRS. We studied 143 patients (mean age, 43.4 years). Low, moderate, and high levels of anxiety were reported by 48.3%, 25.9%, and 25.9% of patients, respectively. Low, moderate, and high levels of depression were reported by 76.2%, 9.1%, and 14.7%. For the combined psychopathology group, 43.3%, 25.9%, and 30% had low, moderate, and high levels. Patients with high anxiety levels reported significant elevations of oropharyngeal symptoms (p = .013) and total symptoms (p = .030) in comparison with the low group. Patients with high depression levels reported higher oropharyngeal (p = .003), systemic (p = .001), and total symptom (p = .003) scores than did the low group. High combined psychopathology scores were associated with elevated facial, oropharyngeal, and systemic scores (p < .05). Regarding medical utilization, high anxiety levels or high combined psychopathology scores were associated with more frequent physician visits (p < .05). A high level of depression was associated with increased antibiotic use, missed workdays, and physician visits (p < .05). High levels of anxiety and depression are common in patients who undergo evaluation for CRS. Psychiatric comorbidity is associated with increased symptoms in CRS and increased health-care utilization. Anxiety and depression should be identified in these patients to structure appropriate treatment.

SHARP2: protein–protein interaction predictions using patch analysis

SHARP2 is a flexible web-based bioinformatics tool for predicting potential protein-protein interaction sites on protein structures. It implements a predictive algorithm that calculates multiple parameters for overlapping patches of residues on the surface of a protein. Six parameters are calculated: solvation potential, hydrophobicity, accessible surface area, residue interface propensity, planarity and protrusion (SHARP2). Parameter scores for each patch are combined, and the patch with the highest combined score is predicted as a potential interaction site. SHARP2 enables users to upload 3D protein structure files in PDB format, to obtain information on potential interaction sites as downloadable HTML tables and to view the location of the sites on the 3D structure using Jmol. The server allows for the input of multiple structures and multiple combinations of parameters. Therefore predictions can be made for complete datasets, as well as individual structures. http://www.bioinformatics.sussex.ac.uk/SHARP2.

Overexpression of Cdc25B, an androgen receptor coactivator, in prostate cancer

Cdc25B is a dual-specific phosphatase that mediates cell cycle progression by activating the cyclin-dependent kinases. It has been shown to possess oncogenic potential. To elucidate its potential contribution to human prostate cancer development, the expression profile of Cdc25B protein in human patients was analysed by immunohistocytochemistry. Cdc25B is frequently overexpressed in human prostate cancer tissues (29 of 30; 97%). In addition, the overexpression is more profound in the tumors of high combined Gleason scores and in late stages. Subsequently, we demonstrated that Cdc25B acts as a coactivator for AR in a hormone-dependent manner in the prostate cancer cell line, LNCaP. This coactivator function, surprisingly, is independent of its cell cycle functions. Cdc25B, on the other hand, directly interacts with AR as evidenced in GST-pull down and mammalian two-hybrid assays. In addition, it is also able to enhance AR-mediated transcription in synergy with other coactivators, including CREB-binding protein (CBP) and p300/CBP associated factor. Therefore, upregulation of Cdc25B in human prostate cancer and its interplay with AR may contribute to prostate cancer development.

Prostate Cancer Aggressiveness Locus on Chromosome 7832-q33 Identified by Linkage and Allelic Imbalance Studies

The biologic aggressiveness of prostate tumors is an important indicator of prognosis. Chromosome 7g32-q33 was recently reported to show linkage to more aggressive prostate cancer, based on Gleason score, in a large sibling pair study. We report confirmation and narrowing of the linked region using finer-scale genotyping. We also report a high frequency of allelic imbalance. (AI) defined within this locus in a series of 48 primary prostate tumors from men unselected for family history or disease status. The highest frequency of AI was observed with adjacent markers D7S2531. (52%) and D7S1804. (36%). These two markers delineated a common region of AI, with 24 tumors exhibiting interstitial AI involving one or both markers. The 1.1-Mb candidate region contains relatively few transcripts. Additionally, we observed positive associations between interstitial AI at D7S1804 and early age at diagnosis. (P=.03) as well as a high combined Gleason score and tumor stage. (P=.06). Interstitial AI at D7S2531 was associated with a positive family history of prostate cancer. (P=.05). These data imply that we have localized a prostate cancer tumor aggressiveness loci to chromosome 7832-q33 that is involved in familial and nonfamilial forms of prostate cancer.

The management of preoperative anxiety in children: an update.

Anxiety in children undergoing surgery is characterized by subjective feelings of tension, apprehension, nervousness, and worry that may be expressed in various forms (1). Postoperative maladaptive behaviors, such as new onset enuresis, feeding difficulties, apathy and withdrawal, and sleep disturbances, may also result from anxiety before surgery. In fact, studies have indicated that up to 60% of all children undergoing surgery may present with negative behavioral changes at 2 wk postoperatively (1,2). Variables such as age, temperament, and anxiety of the child and parent in the preoperative holding area have been identified as predictors for these behavioral changes (1). Extreme anxiety during induction of anesthesia is also associated with an increase of these postoperative negative behavioral changes (3). In addition to behavioral manifestations, preoperative anxiety activates the human stress response, leading to increased serum cortisol, epinephrine, and natural killer cell activity (4,5). This stress response can be activated by many different noxious stimuli including fear, anxiety, pain, cold, major surgery, and infection. The main components of the stress system are the corticotropin-releasing hormone and the locus ceruleus-norepinephrine/autonomic systems and their peripheral effectors, the hypothalamic pituitary-adrenal axis and the limbs of the autonomic system (5). There is also evidence for a bidirectional communication between the neuroendocrine system and the immune system. Stress activates the hypothalamic pituitary-adrenal axis, increases circulating glucocorticoids, and is associated with alterations of immune function and susceptibility to infection and neoplastic disease (6). The human response to surgical stress is characterized by a series of hormonal, immunological, and metabolic changes that together constitute the global surgical stress response (7,8). This perioperative response is considered a homeostatic mechanism for adapting to the perioperative injury. The effects of the surgical stress response, however, may be detrimental: neuroendocrine hormones (e.g., cortisol, catecholamines) and cytokines (e.g., interleukin-6) provoke a negative nitrogen balance and catabolism, delay wound healing, and cause postoperative immunosuppression (7,8). Children are particularly vulnerable to the global surgical stress response because of limited energy reserves, larger brain masses, and obligatory glucose requirements (9). Because acute psychological stress, such as preoperative anxiety, is associated with immediate stress hormone release, the contribution of perioperative psychological factors to the global perioperative stress response cannot be ignored. In adults, increased preoperative anxiety is associated with poor postoperative behavioral and clinical recovery (10,11). As an indicator of the importance of preoperative anxiety, a panel of 72 anesthesiologists recently ranked various anesthesia low-morbidity clinical outcomes based on importance and frequency. The five clinical outcomes with the highest combined score were incisional pain, nausea, vomiting, preoperative anxiety, and discomfort from IV insertion (12). Thus, consensus is evident among anesthesiologists about the need to treat anxiety before surgery. In a modern epidemiological framework, diseases can be characterized in terms of risk factors, interventions, and outcomes. In this update, we will review preoperative anxiety in children using this conceptual framework (Fig. 1).

Which Clinical Anesthesia Outcomes Are Both Common and Important to Avoid? The Perspective of a Panel of Expert Anesthesiologists

Anesthesia groups may need to determine which clinical anesthesia outcomes to track as part of quality improvement efforts.The goal of this study was to poll a panel of expert anesthesiologists to determine which clinical anesthesia outcomes associated with routine outpatient surgery were judged to occur frequently and to be important to avoid. Outcomes scoring highly in both scales could then be prioritized for measurement and improvement in ambulatory clinical practice. A mailed survey instrument instructed panel members to rate 33 clinical anesthesia outcomes in two scales: how frequently they believe the outcomes occur and which outcomes they expect patients find important to avoid. A feedback process (Delphi process) was used to gain consensus rankings of the outcomes for each scale. Importance and frequency scores were then weighted equally to qualitatively rank order the outcomes. Of the 72 anesthesiologists, 56 (78%) completed the questionnaire. The five items with the highest combined score were (in order): incisional pain, nausea, vomiting, preoperative anxiety, and discomfort from IV insertion. To increase quality of care, reducing the incidence and severity of these outcomes should be prioritized. Implications: Expert anesthesiologists reached a consensus on which low-morbidity clinical outcomes are common and important to the patient. The outcomes identified may be reasonable choices to be monitored as part of ambulatory anesthesia clinical quality improvement efforts. (Anesth Analg 1999;88:1085-91)

Which clinical anesthesia outcomes are both common and important to avoid? The perspective of a panel of expert anesthesiologists.

Anesthesia groups may need to determine which clinical anesthesia outcomes to track as part of quality improvement efforts. The goal of this study was to poll a panel of expert anesthesiologists to determine which clinical anesthesia outcomes associated with routine outpatient surgery were judged to occur frequently and to be important to avoid. Outcomes scoring highly in both scales could then be prioritized for measurement and improvement in ambulatory clinical practice. A mailed survey instrument instructed panel members to rate 33 clinical anesthesia outcomes in two scales: how frequently they believe the outcomes occur and which outcomes they expect patients find important to avoid. A feedback process (Delphi process) was used to gain consensus rankings of the outcomes for each scale. Importance and frequency scores were then weighted equally to qualitatively rank order the outcomes. Of the 72 anesthesiologists, 56 (78%) completed the questionnaire. The five items with the highest combined score were (in order): incisional pain, nausea, vomiting, preoperative anxiety, and discomfort from IV insertion. To increase quality of care, reducing the incidence and severity of these outcomes should be prioritized. Expert anesthesiologists reached a consensus on which low-morbidity clinical outcomes are common and important to the patient. The outcomes identified may be reasonable choices to be monitored as part of ambulatory anesthesia clinical quality improvement efforts.

Locating and correcting erroneously recognized portions of utterances by rescoring based on two n-best lists

A method of repairing machine-recognized speech is comprised of the steps of receiving from a recognition engine a first n-best list of hypotheses and scores for each hypothesis generated in response to a primary utterance to be recognized. An error within the hypothesis having the highest score is located. Control signals are generated from the first n-best list which are input to the recognition engine to constrain the generation of a second n-best list of hypotheses, and scores for each hypothesis, in response to an event independent of the primary utterance. The scores for the hypotheses in the first n-best list are combined with the scores for the hypotheses in the second n-best list. The hypothesis having the highest combined score is selected as the replacement for the located error.