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PubMed1999

Robustness and time-scale hierarchy in biological systems.

This study addresses the issue of robustness of biological systems with respect to microscopic parameters, especially the emergence of robustness as a consequence of time-scale hierarchy, applying naive thermodynamic and dynamic assumptions. Theoretical considerations of how the time-scale hierarchy can decouple physiological regulatory mechanisms are illustrated by two model systems involving the photosynthetic apparatus of green plants.

Kinetics↗
PubMed2000

Robustness testing, using experimental design, of a flow-through dissolution method for a product where the actives have markedly differing solubility properties.

The use of experimental design for the robustness testing of a flow-through dissolution method (Ph Eur/USP Apparatus 4) for atovaquone, one of the drug substances in a dual-active anti-malarial tablet formulation, Malarone tablets, is described. This procedure was developed to overcome the suppression of the atovaquone solubility, caused by the presence of the co-drug proguanil hydrochloride and potential imprecision due to the poor solubility of the coating material in the basic dissolution media employed. For this testing a quarter fractional two-level factorial design was applied, assessing six factors in sixteen experiments, with a further six centre points to assess natural experimental variation. Results demonstrate that the method is robust to small changes in all the main factors evaluated at sample times of 30 min or greater. At 15 min, variations in the concentration of sodium hydroxide in the dissolution media, peristaltic pump speed and flow rate were assessed as statistically significant. This observation is a result of the initial steepness of the dissolution release curve and hence these factors are now controlled routinely in the method. Release of this poorly soluble drug is limited at the 45 min time point (Q=75%) according to pharmacopoeial guidelines. The approach may be applied for other dissolution procedures.

Antimalarials↗
PubMed1997

An improved robust hierarchical registration algorithm.

This note describes an improvement to an accurate, robust, and fast registration algorithm (Alexander, M.E. and Somorjai, R.L., Mag. Reson. Imaging, 14:453-468, 1996). A computationally inexpensive preregistration method is proposed, consisting of simply aligning the image centroids, from which estimates of the translation shifts are derived. The method has low sensitivity to noise, and provides starting values of sufficient accuracy for the iterative registration algorithm to allow accurate registration of images that have significant levels of noise and/or large misalignments. Also, it requires a smaller computational effort than the Fourier Phase Matching (FPM) preregistration method used previously. The FPM method provides accurate preregistration for low-noise images, but fails when significant noise is present. For testing the various methods, a 256 x 256 pixel T2*-weighted image was translated, rotated, and scaled to produce large misalignments and occlusion at the image boundaries. The two situations of no noise being present in the images and in which Gaussian noise is added, were tested. After preregistration, the images were registered by applying one or several passes of the iterative algorithm at different levels of preblurring of the input images. Results of using the old and new preregistration methods, as well as no preregistration, are compared for the final accuracy of recovery of registration parameters. In addition, the performances of three robust estimators: Least Median of Squares, Least Trimmed Squares, and Least Winsorized Mean, are compared with those of the nonrobust Least Squares and Woods' methods, and found to converge to correct solutions in cases where the nonrobust methods do not.

Algorithms↗
PubMed2000

Development and validation of a single robust HPLC method for the characterization of a pharmaceutical starting material and impurities from three suppliers using three separate synthetic routes.

Novel approaches to the development of analytical procedures for monitoring incoming starting material in support of chemical/pharmaceutical processes are described. High technology solutions were utilized for timely process development and preparation of high quality clinical supplies. A single robust HPLC method was developed and characterized for the analysis of the key starting material from three suppliers. Each supplier used a different process for the preparation of this material and, therefore, each suppliers' material exhibited a unique impurity profile. The HPLC method utilized standard techniques acceptable for release testing in a QC/manufacturing environment. An automated experimental design protocol was used to characterize the robustness of the HPLC method. The method was evaluated for linearity, limit of quantitation, solution stability, and precision of replicate injections. An LC-MS method that emulated the release HPLC method was developed and the identities of impurities were mapped between the two methods.

Chromatography, High Pressure Liquid↗
PubMed2002

The use of the Box-Behnken experimental design in the optimisation and robustness testing of a capillary electrophoresis method for the analysis of ethambutol hydrochloride in a pharmaceutical formulation.

Box-Behnken experimental designs do not appear to be extensively used in optimisation of analytical methods using capillary electrophoresis (CE). This paper describes the use of the Box-Behnken experimental design to optimise the factors affecting the separation of ethambutol hydrochloride (EB), its impurity 2-amino-1-butanol and the internal standard (phenylephrine hydrochloride) in a CE method for a pharmaceutical tablet assay. The three factors studied simultaneously were: buffer pH, buffer concentration and applied electric field, each at three levels. The method was optimised with respect to three responses: resolution between peaks, theoretical plate count and the migration time of the EB peak. A statistical programme, which applies a multiple response optimisation algorithm, was used to calculate and optimise the three responses simultaneously. The optimum conditions were established to be 58.0 mM sodium borate buffer at pH 9.50 and an applied electric field of 412 V/cm. The robustness of the method was also determined and confirmed using a second Box-Behnken design, as part of the validation exercise. System suitability values for the method were derived from the regression surface analysis. The CE method for a pharmaceutical tablet formulation was further validated according to current regulatory requirements, with respect to linearity and range, precision, specificity, accuracy and limit of quantitation. The optimised method gives a fast and efficient separation under 4 min, with complete resolution between the three peaks, and represents an improvement over the existing USP method. It can be concluded that the Box-Behnken experimental design provides a suitable means of optimising and testing the robustness of a CE pharmaceutical method.

Amino Alcohols↗
PubMed1998

Robustness testing of a liquid chromatography method for the determination of vorozole and its related compounds in oral tablets.

The robustness of a method for the determination of vorozole in oral tablets was examined by applying a two-level, seven factor Plackett-Burman statistical experimental design. Five method variables that are sensitive to variation, especially during method transfer, were evaluated for their influence on the system suitability criteria set in the method procedure and on the analysis time. The method variables were investigated in a specified range above and below the nominal method conditions. They included the concentration of an ion-pairing agent, the percentage organic modifier at the start of the linear gradient, the mobile phase flow rate, the percentage organic modifier at the end of the linear gradient and the pH of the mobile phase. Two dummy factors were included in the design to estimate the experimental error. It was found that none of the five studied variables affected significantly (t-test, alpha = 0.01) the capacity factor, the tailing factor or the analysis time. The resolution of the critical peak pair on the other hand, was significantly influenced by the factor pH. However, the responses for the resolution of all the experimental runs in the design were well above the system suitability limit stated in the normal assay procedure. Therefore, the method can overall be considered robust.

Antineoplastic Agents↗
PubMed2000

Computerized classification of benign and malignant masses on digitized mammograms: a study of robustness.

RATIONALE AND OBJECTIVES: The purpose of this study was to evaluate the robustness of a computerized method developed for the classification of benign and malignant masses with respect to variations in both case mix and film digitization. MATERIALS AND METHODS: The classification method included automated segmentation of mass regions, automated feature-extraction, and automated lesion characterization. The method was evaluated independently with a 110-case database consisting of 50 malignant and 60 benign cases. Mammograms were digitized twice with two different digitizers (Konica and Lumisys). Performance of the method in differentiating benign from malignant masses was evaluated with receiver operating characteristic (ROC) analysis. Effects of variations in both case mix and film digitization on performance of the method also were assessed. RESULTS: Categorization of lesions as malignant or benign with an artificial neural network (or a hybrid) classifier achieved an area under the ROC curve, Az, value of 0.90 (0.94 for the hybrid) on the previous training database in a round-robin evaluation and Az values of 0.82 (0.81) and 0.81 (0.82) on the independent database for the Konica and Lumisys formats, respectively. These differences, however, were not statistically significant (P > .10). CONCLUSION: The computerized method for the classification of lesions on mammograms was robust with respect to variations in case mix and film digitization.

Breast Diseases↗
PubMed2003

Robust registration for computer-integrated orthopedic surgery: laboratory validation and clinical experience.

In order to provide navigational guidance during computer-integrated orthopedic surgery, the anatomy of the patient must first be registered to a medical image or model. A common registration approach is to digitize points from the surface of a bone and then find the rigid transformation that best matches the points to the model by constrained optimization. Many optimization criteria, including a least-squares objective function, perform poorly if the data include spurious data points (outliers). This paper describes a statistically robust, surface-based registration algorithm that we have developed for orthopedic surgery. To find an initial estimate, the user digitizes points from predefined regions of bone that are large enough to reliably locate even in the absence of anatomic landmarks. Outliers are automatically detected and managed by integrating a statistically robust M-estimator with the iterative-closest-point algorithm. Our in vitro validation method simulated the registration process by drawing registration data points from several sets of densely digitized surface points. The method has been used clinically in computer-integrated surgery for high tibial osteotomy, distal radius osteotomy, and excision of osteoid osteoma.

Adolescent↗
PubMed1999

Robust retrieval of three-dimensional structures from image stacks.

Robust high-breakdown-point location estimators are employed to analyze image stacks under the piecewise constant image structure model. To reduce the effect of bias along the Z-axis, the class parameters are extracted using three consecutive slices, The segmentation algorithm first determines the most reliable seed regions, which are then used in a region-growing procedure supported by local evidence. The robustness and stability of the proposed technique is shown with both synthetic and real data, the latter consisting of one MRI and one confocal microscopy set. The performance of the algorithm is consistent with the ground truth obtained with manual segmentation by physicians.

Algorithms↗
PubMed2003

Self-enhanced ligand degradation underlies robustness of morphogen gradients.

Morphogen gradients provide long-range positional information by extending across a developing field. To ensure reproducible patterning, their profile is invariable despite genetic or environmental fluctuations. Common models assume a morphogen profile that decays exponentially. Here, we show that exponential profiles cannot, at the same time, buffer fluctuations in morphogen production rate and define long-range gradients. To comply with both requirements, morphogens should decay rapidly close to their source but at a significantly slower rate over most of the field. Numerical search revealed two network designs that support robustness to fluctuations in morphogen production rate. In both cases, morphogens enhance their own degradation, leading to a higher degradation rate close to their source. This is achieved through reciprocal interactions between the morphogen and its receptor. The two robust networks are consistent with properties of the Wg and Hh morphogens in the Drosophila wing disc and provide novel insights into their function.

Animals↗
PubMed2002

Robust TDT-type candidate-gene association tests.

In studies of association between genetic markers and a disease, the transmission disequilibrium test (TDT) has become a standard procedure. It was introduced originally as a test for linkage in the presence of association and can be used as a test for association under appropriate assumptions. The power of the TDT test for association between a candidate gene and disease depends on the underlying genetic model and the TDT is the optimal test if the additive model holds. Related methods have been obtained for a given mode of inheritance (e.g. dominant or recessive). Quite often, however, the true model is unknown and selection of a single method of analysis is problematic, since use of a test optimal for one genetic model usually leads to a substantial loss of power if another genetic model is the true one. The general approach of efficiency robustness has suggested two types of robust procedures, which we apply to TDT-type association tests. When the plausible range of alternative models is wide (e.g. dominant through recessive) our results indicate that the maximum (MAX) of several test statistics, each of which is optimal for quite different models, has good power under all genetic models. In situations where the set of possible models can be narrowed (e.g. dominant through additive) a simple linear combination also performs well. In general, the MAX has better power properties than the TDT for the study of candidate genes when the mode of inheritance is unknown.

Alleles↗
PubMed2003

Robust classifier for the automated detection of ammonia in heated plumes by passive fourier transform infrared spectrometry.

An automated classification algorithm is implemented for the detection of ammonia vapor in heated plumes by passive Fourier transform infrared (FT-IR) spectrometry. This classification methodology allows the real-time detection of chemical signatures in gaseous effluents such as those generated from industrial processes. The characteristics of real-time implementation and excellent robustness are achieved by an analysis strategy based on the application of band-pass digital filters to short segments of the interferogram data collected by the FT-IR spectrometer, followed by the use of piecewise linear discriminant analysis to obtain a yes/no classification regarding the presence of the analyte signature in the filtered data. The optimal classifier developed through this work is based on only 110 interferogram points and employs a single band-pass filter centered at 945 cm(-)(1) with a pass-band full width at half-maximum of 93 cm(-)(1). The average stop-band attenuation of the optimal filter is 42.1 dB. The robustness of the algorithm is tested by exposing it to chemical releases of sulfur hexafluoride, ethanol, methanol, sulfur dioxide, and hydrogen chloride that were not included in the development of the classifier. Excellent classification performance is demonstrated, with missed ammonia detections occurring at a rate of approximately 1%. The occurrence of false detections is less than 0.1% for SF(6) and less than 0.02% for the other interferences tested.

Air Pollutants, Occupational↗
PubMed2004

A robust technique for assembly of nucleic acid hybridization chips based on electrochemically templated chitosan.

A nucleic acid hybridization assay was assembled onto a robust and readily addressable silicon-based chip using polysaccharide chitosan as a scaffold for the covalent coupling of probe DNA to the chip's surface. Chitosan is a unique polymer, ideally suited for this application because its net charge and solubility are pH dependent. Specifically in this work, gold-patterned electrodes were created using standard photolithographic techniques, chitosan was electrodeposited in a spatially resolved manner onto the polarized electrodes, probe DNA was covalently assembled onto the chitosan, and both DNA:DNA and DNA:mRNA hybridization detection schemes were evaluated. Hybridization of target nucleic acid was quantifiable, reproducible, and robust; the surface was regenerated and rehybridized up to eight times without loss of signal. Finally, transcriptional upregulation of the Escherichia coli chaperone, DnaK, which is an indicator of cellular stress, was observed using the hybridization chip sandwich assay. Thus, this method enables rapid and facile monitoring of gene expression in a format that is reusable and requires minimal reagent quantities.

Chitin↗
PubMed2006

Probabilistic quotient normalization as robust method to account for dilution of complex biological mixtures. Application in 1H NMR metabonomics.

For the analysis of the spectra of complex biofluids, preprocessing methods play a crucial role in rendering the subsequent data analyses more robust and accurate. Normalization is a preprocessing method, which accounts for different dilutions of samples by scaling the spectra to the same virtual overall concentration. In the field of 1H NMR metabonomics integral normalization, which scales spectra to the same total integral, is the de facto standard. In this work, it is shown that integral normalization is a suboptimal method for normalizing spectra from metabonomic studies. Especially strong metabonomic changes, evident as massive amounts of single metabolites in samples, significantly hamper the integral normalization resulting in incorrectly scaled spectra. The probabilistic quotient normalization is introduced in this work. This method is based on the calculation of a most probable dilution factor by looking at the distribution of the quotients of the amplitudes of a test spectrum by those of a reference spectrum. Simulated spectra, spectra of urine samples from a metabonomic study with cyclosporin-A as the active compound, and spectra of more than 4000 samples of control animals demonstrate that the probabilistic quotient normalization is by far more robust and more accurate than the widespread integral normalization and vector length normalization.

Nuclear Magnetic Resonance, Biomolecular↗
PubMed2006

Robust estimation of peptide abundance ratios and rigorous scoring of their variability and bias in quantitative shotgun proteomics.

The abundance ratio between the light and heavy isotopologues of an isotopically labeled peptide can be estimated from their selected ion chromatograms. However, quantitative shotgun proteomics measurements yield selected ion chromatograms at highly variable signal-to-noise ratios for tens of thousands of peptides. This challenge calls for algorithms that not only robustly estimate the abundance ratios of different peptides but also rigorously score each abundance ratio for the expected estimation bias and variability. Scoring of the abundance ratios, much like scoring of sequence assignment for tandem mass spectra by peptide identification algorithms, enables filtering of unreliable peptide quantification and use of formal statistical inference in the subsequent protein abundance ratio estimation. In this study, a parallel paired covariance algorithm is used for robust peak detection in selected ion chromatograms. A peak profile is generated for each peptide, which is a scatterplot of ion intensities measured for the two isotopologues within their chromatographic peaks. Principal component analysis of the peak profile is proposed to estimate the peptide abundance ratio and to score the estimation with the signal-to-noise ratio of the peak profile (profile signal-to-noise ratio). We demonstrate that the profile signal-to-noise ratio is inversely correlated with the variability and bias of peptide abundance ratio estimation.

Algorithms↗
PubMed2006

Robust incision of Benoz[a]pyrene-7,8-dihyrodiol-9,10-epoxide-DNA adducts by a recombinant thermoresistant interspecies combination UvrABC endonuclease system.

Prokaryotic DNA repair nucleases are useful reagents for detecting DNA lesions. UvrABC endonuclease, encoded by the UvrA, UvrB, and UvrC genes can incise DNA containing bulky nucleotide adducts and intrastrand cross-links. UvrA, UvrB, and UvrC were cloned from Bacillus caldotenax (Bca)and UvrC from Thermatoga maritima (Tma), and recombinant proteins were overexpressed in and purified from Escherichia coli. Incision activities of UvrABC composed of all Bca-derived subunits (UvrABC(Bca)) and an interspecies combination UvrABC composed of Bca-derived UvrA and UvrB and Tma-derived UvrC (UvrABC(Tma)) were compared on benoz[a]pyrene-7,8-dihyrodiol-9,10-epoxide (BPDE)-adducted substrates. Both UvrABC(Bca) and UvrABC(Tma) specifically incised both BPDE-adducted plasmid DNAs and site-specifically modified 50-bp oligonucleotides containing a single (+)-trans- or (+)-cis-BPDE adduct. Incision activity was maximal at 55-60 degrees C. However, UvrABC(Tma) was more robust than UvrABC(Bca) with 4-fold greater incision activity on BPDE-adducted oligonucleotides and 1.5-fold greater on [(3)H]BPDE-adducted plasmid DNAs. Remarkably, UvrABC(Bca) incised only at the eighth phosphodiester bond 5' to the BPDE-modified guanosine. In contrast, UvrABC(Tma) performed dual incision, cutting at both the fifth phosphodiester bond 3' and eighth phosphodiester bond 5' from BPDE-modified guanosine. BPDE adduct stereochemistry influenced incision activity, and cis adducts on oligonucleotide substrates were incised more efficiently than trans adducts by both UvrABC(Bca) and UvrABC(Tma). UvrAB-DNA complex formation was similar with (+)-trans- and (+)-cis-BPDE-adducted substrates, suggesting that UvrAB binds both adducts equally and that adduct configuration modifies UvrC recognition of the UvrAB-DNA complex. The dual incision capabilities and higher incision activity of UvrABC(Tma) make it a robust tool for DNA adduct studies.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2004

Electronic spectroscopy, photophysical properties, and emission quenching studies of an oxidatively robust perfluorinated platinum porphyrin.

The highly electron-deficient, beta-octafluorinated meso-tetrakis(pentafluorophenyl)-porphyrin (H(2)F(28)TPP) was metalated with platinum to afford the oxidatively robust luminophore [PtF(28)TPP], and its X-ray structure shows that the porphyrin core exists in a slightly saddle-shaped conformation. The absorption spectrum of [PtF(28)TPP] in CH(2)Cl(2) displays a near-UV Soret band (B) at 383 nm (epsilon = 2.85 x 10(5) dm(3) mol(-1) cm(-1)) and two visible Q(1,0) and Q(0,0) bands at 501 (epsilon = 1.45 x 10(4) dm(3) mol(-1) cm(-1)) and 533 (epsilon = 1.36 x 10(4) dm(3) mol(-1) cm(-1)) nm, respectively. These absorption bands of [PtF(28)TPP] are blue-shifted from those in [PtF(20)TPP] (390, 504, and 538 nm, respectively) and [PtTPP] (401, 509, and 539 nm, respectively). Excitation of [PtF(28)TPP] (complex concentration = 1.5 x 10(-6) mol dm(-3)) in dichloromethane at the Soret or Q(1,0) or Q(0,0) band gave a phosphorescence with peak maximum at 650 nm (lifetime = 5.8 micros) and a weak shoulder at 712 nm. Both the emission lifetime and quantum yield vary with solvent polarity, and plots of tau versus E(K) and Phi versus E(K) (where E(K) is the empirical solvent polarity parameter based on the hypsochromic shift of the longest wavelength absorption of the [Mo(CO)(4)[(C(5)H(4)N)HC[double bond]NCH(2)C(6)H(5)]] complex with increasing solvent polarity; see: Kamlet, M. J.; Abboud, J. L. M.; Taft, R. W. Prog. Phys. Org. Chem. 1981, 13, pp 485-630) show linear correlation, indicating that the emission is sensitive to the local environment/medium. Electrochemical studies on [PtF(28)TPP] by cyclic voltammetry showed no porphyrin-centered oxidation at potential < or = 1.5 V versus Ag/AgNO(3), demonstrating that [PtF(28)TPP] is more resistant toward oxidation than [PtF(20)TPP] (E(1/2) = 1.33 V) and [PtTPP] (E(1/2) = 0.97 V). The porphyrin-centered reduction of [PtF(28)TPP] occurs at -0.75 and -1.18 V, which is anodically shifted from those at -1.06 and -1.55 V in [PtF(20)TPP], and -1.51 V in [PtTPP], respectively. The excited-state reduction potential of [PtF(28)TPP] is estimated to be 1.49 V versus Ag/AgNO(3). Over 97% of the emission intensity of [PtF(28)TPP] was retained after irradiation with a high power mercury arc lamp (500 W) for 14 h, compared to 90% and 12% for [PtF(20)TPP] and [PtTPP], respectively; hence, [PtF(28)TPP] exhibits superior photostability. Quenching of the emission of [PtF(28)TPP] by oxygen, alcohol, catechol, and butylamine reveals that [PtF(28)TPP] is an oxidatively robust material with medium-sensitive photoluminescence properties.

Journal Article↗
PubMed2003

Isolation and crystal structure of a water-soluble iridium hydride: a robust and highly active catalyst for acid-catalyzed transfer hydrogenations of carbonyl compounds in acidic media.

This paper reports the isolation and structural determination of a water-soluble hydride complex [Cp*Ir(III)(bpy)H](+) (1, Cp* = eta(5)-C(5)Me(5), bpy = 2,2'-bipyridine) that serves as a robust and highly active catalyst for acid-catalyzed transfer hydrogenations of carbonyl compounds at pH 2.0-3.0 at 70 degrees C. The catalyst 1 was synthesized from the reaction of a precatalyst [Cp*Ir(III)(bpy)(OH(2))](2+) (2) with hydrogen donors HCOOX (X = H or Na) in H(2)O under controlled conditions (2.0 < pH < 6.0, 25 degrees C) which avoid protonation of the hydrido ligand of 1 below pH ca. 1.0 and deprotonation of the aqua ligand of 2 above pH ca. 6.0 (pK(a) value of 2 = 6.6). X-ray analysis shows that complex 1 adopts a distorted octahedral geometry with the Ir atom coordinated by one eta(5)-Cp*, one bidentate bpy, and one terminal hydrido ligand that occupies a bond position. The isolation of 1 allowed us to investigate the robust ability of 1 in acidic media and reducing ability of 1 in the reaction with carbonyl compounds under both stoichiometric and catalytic conditions. The rate of the acid-catalyzed transfer hydrogenation is drastically dependent on pH of the solution, reaction temperature, and concentration of HCOOH. The effect of pH on the rate of the transfer hydrogenation is rationalized by the pH-dependent formation of 1 and activation process of the carbonyl compounds by protons. High turnover frequencies of the acid-catalyzed transfer hydrogenations at pH 2.0-3.0 are ascribed not only to nucleophilicity of 1 toward the carbonyl groups activated by protons but also to a protonic character of the hydrido ligand of 1 that inhibits the protonation of the hydrido ligand.

Journal Article↗