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PubMed1990

A robust assay for dexamethasone in plasma using a heterologous 125I radioligand and a magnetizable solid-phase antiserum.

An assay using an antiserum raised against a dexamethasone 21-hemisuccinate conjugate and the heterologous radioligand dexamethasone 21-(carboxymethyl) ether was developed, validated, and used to study the pharmacokinetics of this steroid for 12 h following administration to patients with congenital adrenal hyperplasia. Coupling the antiserum to magnetizable cellulose allowed rapid separation of bound/free steroid. A C-21 rather than a C-3 antiserum was used to minimize interference with a main metabolite, 6 beta-hydroxydexamethasone. Close correspondence of assay (0.35 nmol/L) and curve (0.25 nmol/L) sensitivities suggests that interference by matrix effects is minimal. This was confirmed by good agreement in data from the in-house assay and that of a reference procedure. Good precision was demonstrated by the precision profile and Shewhart chart quality control data. The latter also demonstrated the assay was robust and reliable in routine practice.

Adolescent↗

PubMed1992

Robustness of the t test applied to data distorted from normality by floor effects.

In calculus, plaque, and gingivitis trials, measures are taken on subjects both prior to the use of an active treatment and after its use. When the trial is short-term, or when a cleaning of the mouth takes place after the baseline measurement, distributions of such measures (e.g., the Volpe-Manhold score or the Löe and Silness scale) are approximately normally distributed above zero but also can have a proportion of subjects who attain scores of zero. When the effects of an active treatment are compared with those of a control, the two-independent-sample t test can be applied to outcome scores or to differences between the baseline and outcome scores. Robustness of these t tests, in the presence of distributions "distorted" from normality as described, was investigated by computer simulation. In general, both t tests produced actual significance levels which were close to nominal significance levels, even in the presence of small samples and distributions in which as many as 50% of the subjects attained scores of zero.

Clinical Trials as Topic↗

PubMed2004

A novel and robust method for rapid strain estimation in elastography.

In elastography, change in signal shape from tissue deformation and nonaxial tissue motion reduce correlation between the pre- and postcompression echo signals. Appropriate global temporal stretching of postcompression signals can reduce the decorrelation. Adaptive stretching performs a search for the stretch factor that maximizes the correlation between the pre- and postcompression echo signal segments at each data window location. Adaptive stretching is robust but computation intensive. In contrast, global stretching is fast but performs well only in areas where local strains are close to the applied strain. We developed a method that strikes a balance between the speed of global stretching and the performance of adaptive stretching. In this method, several strain maps are computed by performing global stretching with a range of different stretch factors. The area in each computed strain image with strain values closely corresponding to the uniform stretch factor will contain 'good quality' strain estimates. To produce a single elastogram at the end, we identify the strain map with the maximum correlation at each location and the strain value in that strain map at that location is chosen for the combined map. Results from data generated by finite-element simulation and phantom experiments demonstrate that the described strain estimator is significantly less susceptible to signal degradation than conventional strain estimators.

Algorithms↗

PubMedDate not supplied

How robust is the Health Utilities Index Mark 2 utility function?

PURPOSE: The utility function for the Health Utilities Index Mark 2 (HUI2) system is based on preference measurements from a random sample of parents with exclusion of inconsistent respondents. Would results without exclusions or from a different group of parents have differed? METHODS: Scores were obtained from parents of patients (n = 59) undergoing treatment for cancer. Mean scores from the 2 sets of parents were compared:parents of patients and parents from the general population. Three multiattribute utility functions were estimated. Mean scores for HUI2 states using the functions were compared. RESULTS: Most differences in mean scores between different groups were not statistically significant (P < 0.05). Differences in parameter estimates among the 3 utility functions were 0.05 or less. The exponent on the power function for the parent-of-patient group was 2.16, within 6% of that for random sample parents. The intraclass correlation between scores for 144 health states derived from the random-sample-parents and parents-of-patients functions was 0.99; the mean difference per state in scores was 0.018. CONCLUSION: The HUI2 scoring function generalizes well in that different groups of parents give similar results. The HUI2 scoring function is robust in that the functions without and with exclusions generate scores that are very close in value.

Canada↗

PubMed2002

Robust circadian rhythmicity of Per1 and Per2 mutant mice in constant light, and dynamics of Per1 and Per2 gene expression under long and short photoperiods.

The Per1 and Per2 genes are components of the mammalian circadian clock. Mutations in these genes alter phase resetting in response to a nocturnal light pulse, and Per2 mutant mice are known to become arrhythmic in constant darkness. We show that under constant light conditions, Per2 mutant mice exhibit robust activity rhythms as well as body temperature rhythms with a period length that is less than 24 h. In Per1 mutants, the period length of both activity and body temperature rhythms is longer than 24 h in constant light. Per1 mutants prolong their period length (tao) when illuminance is increased, whereas Per2 mutants shorten their endogenous period. Additionally, the authors show that the circadian pattern of Per1 and Per2 gene expression in mice is modified under different photoperiods and that there is a mutual influence of these genes on their timing of expression. We propose that, in mice, the phase relationship between Per1 and Per2 gene expression might be critical for transducing day length information to the organism. Per1 could be part of a morning oscillator tracking dawn, and Per2 could be part of an evening oscillator tracking dusk.

Animals↗

PubMedDate not supplied

A patient satisfaction theory and its robustness across gender in emergency departments: a multigroup structural equation modeling investigation.

This investigation tested the patient-centered Primary Provider Theory of Patient Satisfaction across gender in national random samples of emergency patients. Using multigroup structural equation modeling, the results supported the model's robustness. Physician service, waiting time, and nursing satisfaction explained 48%, 41%, and 11% of overall satisfaction plus 92% and 93% of female and male satisfaction, respectively. Unit increases in physician service satisfaction increased waiting time, nursing, and overall satisfaction by 0.991, 0.844, and 1.031 units, respectively. Unit increases in waiting time satisfaction increased nursing and overall satisfaction by 0.417 and 0.685 units, respectively. A unit increase in nursing satisfaction increased overall service satisfaction by 0.221 units. The investigation offers an alternative paradigm for measuring and achieving emergency department satisfaction, hierarchically related to patient expectations, where the primary provider has the greatest clinical utility to patients, followed by waiting for the primary provider, and then by nursing service.

Adult↗

PubMed2000

A novel and robust homogeneous fluorescence-based assay using nanoparticles for pharmaceutical screening and diagnostics.

We have established a new type of homogeneous immunoassay based on nanoparticles (nanoparticle immunoassay, or NPIA) being analyzed using fluorescence intensity distribution analysis (FIDA). This method allows the characterization of single fluorescently labeled molecules or particles with respect to their molecular brightness and concentration. Upon binding of conjugates to molecules coupled to the nanoparticle surface, the brightness of the complex scales with the number of bound conjugates. The complexes can then be distinguished accurately from free conjugate and concentrations of free and bound molecules can be determined reliably. In this study we present various examples of NPIAs where capture antibodies were linked to the nanoparticles, which were either artificial beads or bacteria. Two assay formats have been developed; first, direct labeling of the conjugate was used to quantitate free antigen through competition experiments, and second, an antigen-directed antibody was labeled to establish an assay similar to a sandwich ELISA setup. The major advantages of a NPIA are the robustness and high signal-to-noise ratio at short measurement times, as demonstrated with a miniaturized experiment in a Nanocarriertrade mark holding a volume of 1 microl/well. In addition to the good data quality, NPIAs are straightforward to perform because they require no washing steps. NPIAs open new dimensions for high throughput pharmaceutical screening and diagnostics. Assay development times can be reduced significantly because of a simple toolbox principle that is applicable to most types of assays.

Chorionic Gonadotropin↗

PubMed2004

Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with recognized variability in clinical outcome, genetic features, and cells of origin. To date, transcriptional profiling has been used to highlight similarities between DLBCL tumor cells and normal B-cell subtypes and associate genes and pathways with unfavorable outcome. To identify robust and highly reproducible DL-BCL subtypes with comprehensive transcriptional signatures, we used a large series of newly diagnosed DLBCLs, whole genome arrays, and multiple clustering methods. Tumors were also analyzed for known common genetic abnormalities in DLBCL. There were 3 discrete subsets of DLBCL-"oxidative phosphorylation," "B-cell receptor/proliferation," and "host response" (HR)-identified characterized using gene set enrichment analysis and confirmed in an independent series. HR tumors had increased expression of T/natural killer cell receptor and activation pathway components, complement cascade members, macrophage/dendritic cell markers, and inflammatory mediators. HR DLB-CLs also contained significantly higher numbers of morphologically distinct CD2+/CD3+ tumor-infiltrating lymphocytes and interdigitating S100+/gamma interferon-induced lysosomal transferase-positive (GILT+) CD1a-/CD123- dendritic cells. The HR cluster shared features of histologically defined T-cell/histiocyte-rich B-cell lymphoma, including fewer genetic abnormalities, younger age at presentation, and frequent splenic and bone marrow involvement. These studies identify tumor microenvironment and host inflammatory response as defining features in DLBCL and suggest rational treatment targets in specific DLBCL subsets.

Cluster Analysis↗

PubMed2007

Slow disease progression and robust therapy-mediated CD4+ T-cell recovery are associated with efficient thymopoiesis during HIV-1 infection.

In chronic HIV infection, most untreated patients lose naive CD4+ and CD8+ T cells, whereas a minority preserve them despite persistent high viremia. Although antiretroviral therapy (ART)-mediated viral suppression generally results in a rise of naive and total CD4+ T cells, certain patients experience very little or no T-cell reconstitution. High peripheral T-cell activation has been linked to poor clinical outcomes, interfering with previous evaluations of thymic function in disease progression and therapy-mediated T-cell recovery. To circumvent this, we used the sj/betaTREC ratio, a robust index of thymopoiesis that is independent of peripheral T-cell proliferation, to evaluate the thymic contribution to the preservation and restoration of naive CD4+ T cells. We show that the loss of naive and total CD4+ T cells is the result of or is exacerbated by a sustained thymic defect, whereas efficient thymopoiesis supports naive and total CD4+ T-cell maintenance in slow progressor patients. In ART-treated patients, CD4+ T-cell recovery was associated with the normalization of thymopoiesis, whereas the thymic defect persisted in aviremic patients who failed to recover CD4+ T-cell counts. Overall, we demonstrate that efficient thymopoiesis is key in the natural maintenance and in therapy-mediated recovery of naive and total CD4+ T cells.

Adult↗

PubMed2003

Exhaled breath condensate pH is a robust and reproducible assay of airway acidity.

Exhaled breath condensate (EBC) pH is low in several lung diseases and it normalises with therapy. The current study examined factors relevant to EBC pH monitoring. Intraday and intraweek variability were studied in 76 subjects. The pH of EBC collected orally and from isolated lower airways was compared in an additional 32 subjects. Effects of ventilatory pattern (hyperventilation/hypoventilation), airway obstruction after methacholine, temperature (-44 to +13 degrees C) and duration of collection (2-7 min), and duration of sample storage (up to 2 yrs) were examined. All samples were collected with a disposable condensing device, and de-aerated with argon until pH measurement stabilised. Mean EBC pH (n=76 subjects, total samples=741) was 7.7+/-0.49 (mean+/-SD). Mean intraweek and intraday coefficients of variation were 4.5% and 3.5%. Control of EBC pH appears to be at the level of the lower airway. Temperature of collection, duration of collection and storage, acute airway obstruction, subject age, saliva pH, and profound hyperventilation and hypoventilation had no effect on EBC pH. The current authors conclude that in health, exhaled breath condensate pH is slightly alkaline, held in a narrow range, and is controlled by lower airway source fluid. Measurement of exhaled breath condensate pH is a simple, robust, reproducible and relevant marker of disease.

Acid-Base Equilibrium↗

PubMed2005

JACOP: a simple and robust method for the automated classification of protein sequences with modular architecture.

BACKGROUND: Whole-genome sequencing projects are rapidly producing an enormous number of new sequences. Consequently almost every family of proteins now contains hundreds of members. It has thus become necessary to develop tools, which classify protein sequences automatically and also quickly and reliably. The difficulty of this task is intimately linked to the mechanism by which protein sequences diverge, i.e. by simultaneous residue substitutions, insertions and/or deletions and whole domain reorganisations (duplications/swapping/fusion). RESULTS: Here we present a novel approach, which is based on random sampling of sub-sequences (probes) out of a set of input sequences. The probes are compared to the input sequences, after a normalisation step; the results are used to partition the input sequences into homogeneous groups of proteins. In addition, this method provides information on diagnostic parts of the proteins. The performance of this method is challenged by two data sets. The first one contains the sequences of prokaryotic lyases that could be arranged as a multiple sequence alignment. The second one contains all proteins from Swiss-Prot Release 36 with at least one Src homology 2 (SH2) domain--a classical example for proteins with modular architecture. CONCLUSION: The outcome of our method is robust, highly reproducible as shown using bootstrap and resampling validation procedures. The results are essentially coherent with the biology. This method depends solely on well-established publicly available software and algorithms.

Algorithms↗

PubMed2006

Methodological study of affine transformations of gene expression data with proposed robust non-parametric multi-dimensional normalization method.

BACKGROUND: Low-level processing and normalization of microarray data are most important steps in microarray analysis, which have profound impact on downstream analysis. Multiple methods have been suggested to date, but it is not clear which is the best. It is therefore important to further study the different normalization methods in detail and the nature of microarray data in general. RESULTS: A methodological study of affine models for gene expression data is carried out. Focus is on two-channel comparative studies, but the findings generalize also to single- and multi-channel data. The discussion applies to spotted as well as in-situ synthesized microarray data. Existing normalization methods such as curve-fit ("lowess") normalization, parallel and perpendicular translation normalization, and quantile normalization, but also dye-swap normalization are revisited in the light of the affine model and their strengths and weaknesses are investigated in this context. As a direct result from this study, we propose a robust non-parametric multi-dimensional affine normalization method, which can be applied to any number of microarrays with any number of channels either individually or all at once. A high-quality cDNA microarray data set with spike-in controls is used to demonstrate the power of the affine model and the proposed normalization method. CONCLUSION: We find that an affine model can explain non-linear intensity-dependent systematic effects in observed log-ratios. Affine normalization removes such artifacts for non-differentially expressed genes and assures that symmetry between negative and positive log-ratios is obtained, which is fundamental when identifying differentially expressed genes. In addition, affine normalization makes the empirical distributions in different channels more equal, which is the purpose of quantile normalization, and may also explain why dye-swap normalization works or fails. All methods are made available in the aroma package, which is a platform-independent package for R.

Algorithms↗

PubMed2006

More robust detection of motifs in coexpressed genes by using phylogenetic information.

BACKGROUND: Several motif detection algorithms have been developed to discover overrepresented motifs in sets of coexpressed genes. However, in a noisy gene list, the number of genes containing the motif versus the number lacking the motif might not be sufficiently high to allow detection by classical motif detection tools. To still recover motifs which are not significantly enriched but still present, we developed a procedure in which we use phylogenetic footprinting to first delineate all potential motifs in each gene. Then we mutually compare all detected motifs and identify the ones that are shared by at least a few genes in the data set as potential candidates. RESULTS: We applied our methodology to a compiled test data set containing known regulatory motifs and to two biological data sets derived from genome wide expression studies. By executing four consecutive steps of 1) identifying conserved regions in orthologous intergenic regions, 2) aligning these conserved regions, 3) clustering the conserved regions containing similar regulatory regions followed by extraction of the regulatory motifs and 4) screening the input intergenic sequences with detected regulatory motif models, our methodology proves to be a powerful tool for detecting regulatory motifs when a low signal to noise ratio is present in the input data set. Comparing our results with two other motif detection algorithms points out the robustness of our algorithm. CONCLUSION: We developed an approach that can reliably identify multiple regulatory motifs lacking a high degree of overrepresentation in a set of coexpressed genes (motifs belonging to sparsely connected hubs in the regulatory network) by exploiting the advantages of using both coexpression and phylogenetic information.

Algorithms↗

PubMed2004

Accurate and robust phylogeny estimation based on profile distances: a study of the Chlorophyceae (Chlorophyta).

BACKGROUND: In phylogenetic analysis we face the problem that several subclade topologies are known or easily inferred and well supported by bootstrap analysis, but basal branching patterns cannot be unambiguously estimated by the usual methods (maximum parsimony (MP), neighbor-joining (NJ), or maximum likelihood (ML)), nor are they well supported. We represent each subclade by a sequence profile and estimate evolutionary distances between profiles to obtain a matrix of distances between subclades. RESULTS: Our estimator of profile distances generalizes the maximum likelihood estimator of sequence distances. The basal branching pattern can be estimated by any distance-based method, such as neighbor-joining. Our method (profile neighbor-joining, PNJ) then inherits the accuracy and robustness of profiles and the time efficiency of neighbor-joining. CONCLUSIONS: Phylogenetic analysis of Chlorophyceae with traditional methods (MP, NJ, ML and MrBayes) reveals seven well supported subclades, but the methods disagree on the basal branching pattern. The tree reconstructed by our method is better supported and can be confirmed by known morphological characters. Moreover the accuracy is significantly improved as shown by parametric bootstrap.

Animals↗

PubMed2004

Upstream plasticity and downstream robustness in evolution of molecular networks.

BACKGROUND: Gene duplication followed by the functional divergence of the resulting pair of paralogous proteins is a major force shaping molecular networks in living organisms. Recent species-wide data for protein-protein interactions and transcriptional regulations allow us to assess the effect of gene duplication on robustness and plasticity of these molecular networks. RESULTS: We demonstrate that the transcriptional regulation of duplicated genes in baker's yeast Saccharomyces cerevisiae diverges fast so that on average they lose 3% of common transcription factors for every 1% divergence of their amino acid sequences. The set of protein-protein interaction partners of their protein products changes at a slower rate exhibiting a broad plateau for amino acid sequence similarity above 70%. The stability of functional roles of duplicated genes at such relatively low sequence similarity is further corroborated by their ability to substitute for each other in single gene knockout experiments in yeast and RNAi experiments in a nematode worm Caenorhabditis elegans. We also quantified the divergence rate of physical interaction neighborhoods of paralogous proteins in a bacterium Helicobacter pylori and a fly Drosophila melanogaster. However, in the absence of system-wide data on transcription factors' binding in these organisms we could not compare this rate to that of transcriptional regulation of duplicated genes. CONCLUSIONS: For all molecular networks studied in this work we found that even the most distantly related paralogous proteins with amino acid sequence identities around 20% on average have more similar positions within a network than a randomly selected pair of proteins. For yeast we also found that the upstream regulation of genes evolves more rapidly than downstream functions of their protein products. This is in accordance with a view which puts regulatory changes as one of the main driving forces of the evolution. In this context a very important open question is to what extent our results obtained for homologous genes within a single species (paralogs) carries over to homologous proteins in different species (orthologs).

Animals↗

PubMed2005

A robust method for the amplification of RNA in the sense orientation.

BACKGROUND: Small quantities of RNA (1-4 microg total RNA) available from biological samples frequently require a single round of amplification prior to analysis, but current amplification strategies have limitations that may restrict their usefulness in downstream genomic applications. The Eberwine amplification method has been extensively validated but is limited by its ability to produce only antisense RNA. Alternatives lack extensive validation and are often confounded by problems with bias or yield attributable to their greater biological and technical complexity. RESULTS: To overcome these limitations, we have developed a straightforward and robust protocol for amplification of RNA in the sense orientation. This protocol is based upon Eberwine's method but incorporates elements of more recent amplification techniques while avoiding their complexities. Our technique yields greater than 100-fold amplification, generates long transcript, and produces mRNA that is well suited for use with microarray applications. Microarrays performed with RNA amplified using this protocol demonstrate minimal amplification bias and high reproducibility. CONCLUSION: The protocol we describe here is readily adaptable for the production of sense or antisense, labeled or unlabeled RNA from intact or partially-degraded prokaryotic or eukaryotic total RNA. The method outperforms several commercial RNA amplification kits and can be used in conjunction with a variety of microarray platforms, such as cDNA arrays, oligonucleotide arrays, and Affymetrix GeneChip arrays.

Algorithms↗

PubMed2026

Robust human genetic evidence supporting causal effects of FGF21 on reducing alcohol consuming behaviours.

BACKGROUND: Alcohol use disorder (AUD) represents a tremendous societal burden, yet few efficacious therapies are available and widely used. Pre-clinical and human observational data support fibroblast growth factor 21 (FGF21) as a promising therapeutic target for the treatment of AUD. The objective of this study is to identify a robust genetic instrument for FGF21 agonism and leverage it to explore the effects of FGF21 agonism on AUD and related traits, as well as metabolic outcomes more widely. METHODS: We first compared associations with the positive control outcomes of liver fat and liver cirrhosis risk for the FGF21 cis-protein quantitative trait locus (cis-pQTL) (rs838131) to those for the common allele FGF21 L174P missense variant (rs739320). Having identified the L174P missense variant as a plausible genetic instrument, we subsequently performed association analyses investigating effects on AUD, related traits, and metabolic outcomes more widely. Finally, we performed colocalisation analyses to test whether observed association results reflect a causal mechanism that overlaps with the clinical effects of FGF21 on liver fat and liver cirrhosis. RESULTS: Consistent association and colocalisation evidence support a protective association between genetically predicted FGF21 agonism and alcohol consumption (association p = 1 × 10-18, colocalisation posterior probability = 0.90), problematic alcohol use (association p = 0.02, posterior probability = 0.64), and AUD (association p = 9 × 10-8, posterior probability = 0.97). Similar evidence was also observed for favourable effects of FGF21 on improving kidney function, lowering triglyceride levels, lowering proportional energy intake from carbohydrates, increasing proportional energy intake from protein and fat, increasing body weight and lowering waist-to-hip ratio. CONCLUSIONS: This study identifies a genetic instrument for FGF21 effects to provide causal human evidence supporting favourable effects of FGF21 analogues for the treatment of AUD and related traits, as well as on metabolic outcomes more broadly. Further clinical study is duly warranted.

Humans↗

PubMed1997

Robust leptin secretory responses to dexamethasone in obese subjects.

Although leptin reverses obesity in rodents, its function and regulation in humans are unknown. Glucocorticoids have been reported to stimulate leptin production in both rodents and humans, but data assessing the effect of obesity on dynamic leptin secretory responses are unavailable. We, therefore, studied 52 lean and obese subjects [20 men and 32 women; aged 19-84 yr; body mass index (BMI) range, 16-47 kg/m2] randomized to treatment with dexamethasone (total dose, 10 mg/4 days) or placebo. Compared with placebo, dexamethasone increased (P = 0.0001) plasma leptin levels by 64-111% above baseline values within 2-4 days. The increases occurred in all ages, showed no sexual dimorphism, and were particularly robust in obese subjects. After dexamethasone treatment, significant interactions were observed between the change in plasma leptin and BMI (P = 0.0001), baseline plasma leptin (P = 0.0006) and plasma dexamethasone levels (P = 0.04), but not age (P = 0.28); an apparent interaction with plasma insulin no longer was significant after controlling for BMI. These results confirm dexamethasone-induced hyperleptinemia in humans and further demonstrate that the response is not defective in obesity.

Adult↗