An improved machine learning protocol for the identification of correct Sequest search results

Background  

Mass spectrometry has become a standard method by which the proteomic profile of cell or tissue samples is characterized. To fully take advantage of tandem mass spectrometry (MS/MS) techniques in large scale protein characterization studies robust and consistent data analysis procedures are crucial. In this work we present a machine learning based protocol for the identification of correct peptide-spectrum matches from Sequest database search results, improving on previously published protocols.     

Osteoarthritis subpopulations and implications for clinical trial design

Treatment guidelines for osteoarthritis have stressed the need for research on clinical predictors of response to different treatments. However, identifying such clinical predictors of response is less easy than it seems, and there is not a given classification of osteoarthritis subpopulations. This review article highlights the key methodical issues when analyzing and designing clinical studies to detect important subgroups with respect to treatment effect. In addition, we discuss the main osteoarthritis subpopulations and give examples of how specific treatment effects in these subpopulations have been assessed.     

SParSE++: improved event-based stochastic parameter search

Background

Despite the increasing availability of high performance computing capabilities, analysis and characterization of stochastic biochemical systems remain a computational challenge. To address this challenge, the Stochastic Parameter Search for Events (SParSE) was developed to automatically identify reaction rates that yield a probabilistic user-specified event. SParSE consists of three main components: the multi-level cross-entropy method, which identifies biasing parameters to push the system toward the event of interest, the related inverse biasing method, and an optional interpolation of identified parameters. While effective for many examples, SParSE depends on the existence of a sufficient amount of intrinsic stochasticity in the system of interest. In the absence of this stochasticity, SParSE can either converge slowly or not at all.

Results

We have developed SParSE++, a substantially improved algorithm for characterizing target events in terms of system parameters. SParSE++ makes use of a series of novel parameter leaping methods that accelerate the convergence rate to the target event, particularly in low stochasticity cases. In addition, the interpolation stage is modified to compute multiple interpolants and to choose the optimal one in a statistically rigorous manner. We demonstrate the performance of SParSE++ on four example systems: a birth-death process, a reversible isomerization model, SIRS disease dynamics, and a yeast polarization model. In all four cases, SParSE++ shows significantly improved computational efficiency over SParSE, with the largest improvements resulting from analyses with the strictest error tolerances.

Conclusions

As researchers continue to model realistic biochemical systems, the need for efficient methods to characterize target events will grow. The algorithmic advancements provided by SParSE++ fulfill this need, enabling characterization of computationally intensive biochemical events that are currently resistant to analysis.

     

Interpreting Images: Diagnostic Skill In The Genetics Clinic

The diagnosis of rare genetic disorders involves classifying patients on the basis of clinical understandings of the relationship between visible, measurable characteristics (the phenotype) and an underlying genetic characterization (the genotype). Diagnosis is performed through the routine ritual observation and interpretation of images of patients in relation to their clinical features and test results. In this process, which is mediated by senior clinicians, the experience of the effect of a patient's image is integral to the skilful elicitation of a diagnosis. Such skill develops over time, through regular participation in diagnostic performances. I suggest that, from this perspective, genetic diagnosis is a clinical process rather than a form of genetic reductionism and that assumptions about 'geneticization' require further exploration. The article also shows that participant observation and a cross-cultural mode of analysis can contribute to documenting and interpreting these processes.     

Adjuvant liver perfusion in colorectal cancer: initial results of a clinical trial.

Fifty consecutive patients with colorectal cancer but no evidence of secondary deposits in the liver were included in an ongoing controlled clinical trial of adjuvant liver perfusion aimed at reducing the incidence of hepatic metastases. All patients had their primary tumour resected in the standard way. Twenty-six of the patients served as controls, and 24 received fluorouracil, 1 g daily, as a continuous infusion into the portal venous system during the first seven days after operation. The patients were matched for age, sex, and site and stage of the disease. The immediate postoperative mortality and morbidity did not differ significantly between the two groups. During the follow-up period (mean duration 15.5 months), however, six deaths occurred in the control group and only one in the perfusion group. At necropsy four of the controls had multiple liver metastases. Two of the surviving controls developed evidence of liver metastases, and two had a local recurrence. No patient in the perfusion group developed evidence of hepatic metastases. These initial results suggest that adjuvant portal venous perfusion with fluorouracil may reduce the incidence of liver metastases in colorectal cancer.     

In search of improved fat transfer viability: a quantitative analysis of the role of centrifugation and harvest site

Fat grafting is an unpredictable procedure that continues to challenge the field of plastic surgery due to irregular resorption. Applications for this procedure are broad in both reconstructive and cosmetic plastic surgery. Fat grafts are carefully obtained and manipulated to obtain better graft takes and results, yet there is no universal agreement on what constitutes an ideal methodology. The present study examines adipocyte viability from four commonly used donor sites in five subjects. No statistical differences in adipocyte viability were demonstrated among abdominal fat, thigh fat, flank fat, or knee fat donor sites that were immediately removed and untreated (p < 0.225). In addition, no differences were observed in representative tissue samples that were removed and centrifuged (thigh, p = 0.508; knee, p = 0.302; flank, p = 0.088; abdomen, p = 0.533). On the basis of these quantitative data, neither harvest location nor centrifugation demonstrated any advantage in terms of lipocyte viability. Fat tissue transfers from these common sites may be considered equal, and centrifugation does not appear to enhance immediate fat tissue viability before implantation.     

In search of morphogenes

May we talk about morphogenes as it is actually done about oncogenes? The author reviews some recent experimental discoveries which launch embryology on a new way: rethinking mitosis, studying cell movement and adhesion, neuronal migration, the role of gap-junctions, cell-death programmation. Embryology and genetics are today converging on identic aims, particularly in the fields of the homeotic genes and of transgenic animals.     

Analysis of two-period crossover design in a multicenter clinical trial

A technique is discussed for analyzing a two-period crossover design for a multicenter trial using identical study protocols. The technique is a modification of the analysis originally proposed by Grizzle (1965, Biometrics 21, 467-480; 1974, Biometrics 30, 727) for analyzing a two-period crossover design when study is not a factor. A mixed model using the first baseline as a covariate is analyzed to increase the power of the test of significance of the treatment-by-period interaction. The baseline values are also used in a preliminary test.