| 1. |
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| 2. |
- Smith, Jennifer A, et al.
(author)
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Genome-wide association study identifies 74 loci associated with educational attainment
- 2016
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In: Nature (London). - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 533:7604, s. 539-542
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Journal article (peer-reviewed)abstract
- Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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| 3. |
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| 4. |
- Artursson, Tom, et al.
(author)
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Study of Preprocessing Methods for the Determination of Crystalline Phases in Binary Mixtures of Drug Substances by X-ray Powder Diffraction and Multivariate Calibration
- 2000
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In: Applied Spectroscopy. - : SAGE Publications. - 0003-7028 .- 1943-3530. ; 54:8, s. 272A-301A
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Journal article (peer-reviewed)abstract
- In this paper, various preprocessing methods were tested on data generated by X-ray powder diffraction (XRPD) in order to enhance the partial least-squares (PLS) regression modeling performance. The preprocessing methods examined were 22 different discrete wavelet transforms, Fourier transform, Savitzky-Golay, orthogonal signal correction (OSC), and combinations of wavelet transform and OSC, and Fourier transform and OSC. Root mean square error of prediction (RMSEP) of an independent test set was used to measure the performance of the various preprocessing methods. The best PLS model was obtained with a wavelet transform (Symmlet 8), which at the same time compressed the data set by a factor of 9.5. With the use of wavelet and X-ray powder diffraction, concentrations of less than 10% of one crystal from could be detected in a binary mixture. The linear range was found to be in the range 10-70% of the crystalline form of phenacetin, although semiquantitative work could be carried out down to a level of approximately 2%. Furthermore, the wavelet-pretreated models were able to handle admixtures and deliberately added noise.
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| 5. |
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| 6. |
- Forshed, Jenny, et al.
(author)
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Enhanced multivariate analysis by correlation scaling and fusion of LC/MS and 1H-NMR data
- 2007
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In: Chemometrics and Intelligent Laboratory Systems. - : Elsevier B.V. - 0169-7439 .- 1873-3239. ; 85:2, s. 179-185
-
Journal article (peer-reviewed)abstract
- A method to enhance the multivariate data interpretation of, for instance, metabolic profiles is presented. This was done by correlation scaling of 1H NMR data by the time pattern of drug metabolite peaks identified by LC/MS, followed by parallel factor analysis (PARAFAC). The variables responsible for the discrimination between the dosed and control rats in this model were then eliminated in both data sets. Next, an additional PARAFAC analysis was performed with both LC/MS and 1H NMR data, fused by outer product analysis (OPA), to obtain sufficient class separation. The loadings from this second PARAFAC analysis showed new peaks discriminating between the classes. The time trajectories of these peaks did not agree with the drug metabolites and were detected as possible candidates for markers. These data analyses were also compared with the PARAFAC analysis of raw data, which showed very much the same loading peaks as for the correlation-scaled data, although the intensities differed. Elimination of the variables correlated with the drug metabolites was therefore necessary to be able to select the peaks which were not drug metabolites and which discriminated between the classes.1
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| 7. |
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| 8. |
- Forshed, Jenny, et al.
(author)
-
Evaluation of different techniques for fusion of LC/MS and 1HNMR data
- 2007
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In: Chemometrics and Intelligent Laboratory Systems. - 0169-7439 .- 1873-3239. ; 85:1, s. 102-109
-
Journal article (peer-reviewed)abstract
- In the analyses of highly complex samples (for example, metabolic fingerprinting), the data might not suffice for classification when using only a single analytical technique. Hence, the use of two complementary techniques, e.g., LUMS and H-1-NMR, might be advantageous. Another possible advantage from using two different techniques is the ability to verify the results (for instance, by verifying a time trend of a metabolic pattern). In this work, both LC/MS and H-1-NMR data from analysis of rat urine have been used to obtain metabolic fingerprints. A comparison of three different methods for data fusion of the two data sets was performed and the possibilities and difficulties associated with data fusion were discussed. When comparing concatenated data, full hierarchical modeling, and batch modeling, the first two approaches were found to be the most successful. Different types of block scaling and variable scaling were evaluated and the optimal scaling for each case was found by cross validation. Validations of the final models were performed by means of an external test set.(2)
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| 9. |
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| 10. |
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| 11. |
- Forshed, Jenny, 1972-
(author)
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Processing and analysis of NMR data : Impurity determination and metabolic profiling
- 2005
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Doctoral thesis (other academic/artistic)abstract
- This thesis describes the use of nuclear magnetic resonance (NMR) spectrometry as an analytical tool. The theory of NMR spectroscopy in general and quantitative NMR spectrometry (qNMR) in particular is described and the instrumental properties and parameter setups for qNMR measurements are discussed. Examples of qNMR are presented by impurity determination of pharmaceutical compounds and analysis of urine samples from rats fed with either water or a drug (metabolic profiling). The instrumental parameter setup of qNMR and traditional data pre-treatments are examined. Spectral smoothing by convolution with a triangular function, which is an unusual application in this context, was shown to be successful regarding the sensitivity and robustness of the method in paper II. In addition, papers III and IV comprise the field of peak alignment, especially designed for 1H-NMR spectra of urine samples. This is an important preprocessing tool when multivariate analysis is to be applied. A novel peak alignment method was developed and compared to the traditional bucketing approach and a conceptually different alignment method.Univariate, multivariate, linear and nonlinear data analyses were applied to qNMR data. In papers I–II, calibration models were created to examine the potential of qNMR for these applications. The data analysis in papers III–VI was mainly explorative. The potential of data fusion and data correlation was examined in order to increase the possibilities of analysing the highly complex samples from metabolic profiling (papers V–VI). Data from LC/MS analysis of the same samples were used with the 1H-NMR data in different ways. Correlation analyses between the 1H-NMR data and the drug metabolites identified from the LC/MS data were also performed. In this process, data fusion proved to be a valuable tool.
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| 12. |
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| 13. |
- Grey, Carl, et al.
(author)
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Development of a high performance anion exchange chromatography analysis for mapping of oligosaccharides
- 2009
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In: Journal of chromatography. B. - : Elsevier BV. - 1570-0232 .- 1873-376X. ; 877:20-21, s. 1827-1832
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Journal article (peer-reviewed)abstract
- In the present study a HPAEC-PAD method is described that was developed for monitoring the consistency of N-glycosylation during the production and purification of recombinant proteins and monoclonal antibodies. The method successfully separated 18 neutral and sialylated oligosaccharides. Results obtained were compared with MALDI-TOF MS and it was shown that both methods gave similar results. in addition, a method validation was performed showing that the HPAEC-PAD analysis was well suited for the mapping and characterization of oligosaccharides. The method was found to be robust and additionally the precision was significantly better compared to the MALDI-TOF MS method.
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| 14. |
- Harang, Valérie, 1966-
(author)
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Aspects of Optimisation of Separation of Drugs by Chemometrics
- 2003
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Doctoral thesis (other academic/artistic)abstract
- Statistical experimental designs have been used for method development and optimisation of separation. Two reversed phase HPLC methods were optimised. Parameters such as the pH, the amount of tetrabutylammonium (TBA; co-ion) and the gradient slope (acetonitrile) were investigated and optimised for separation of erythromycin A and eight related compounds. In the second method, a statistical experimental design was used, where the amounts of acetonitrile and octane sulphonate (OSA; counter ion) and the buffer concentration were studied, and generation of an α-plot with chromatogram simulations optimised the separation of six analytes.The partial filling technique was used in capillary electrophoresis to introduce the chiral selector Cel7A. The effect of the pH, the ionic strength and the amount of acetonitrile on the separation and the peak shape of R- and S-propranolol were investigated.Microemulsion electrokinetic chromatography (MEEKC) is a technique similar to micellar electrokinetic chromatography (MEKC), except that the microemulsion has a core of tiny droplets of oil inside the micelles. A large number of factors can be varied when using this technique. A screening design using the amounts of sodium dodecyl sulphate (SDS), Brij 35, 1-butanol and 2-propanol, the buffer concentration and the temperature as factors revealed that the amounts of SDS and 2-propanol were the most important factors for migration time and selectivity manipulation of eight different compounds varying in charge and hydrophobicity. SDS and 2-propanol in the MEEKC method were further investigated in a three-level full factorial design analysing 29 different compounds sorted into five different groups. Different optimisation strategies were evaluated such as generating response surface plots of the selectivity/resolution of the most critical pair of peaks, employing chromatographic functions, simplex optimisation in MODDE and 3D resolution maps in DryLab™.Molecular descriptors were fitted in a PLS model to retention data from the three-level full factorial design of the MEEKC system. Two different test sets were used to study the predictive ability of the training set. It was concluded that 86 – 89% of the retention data could be predicted correctly for new molecules (80 – 120% of the experimental values) with different settings of SDS and 2-propanol.Statistical experimental designs and chemometrics are valuable tools for the development and optimisation of analytical methods. The same chemometric strategies can be employed for all types of separation techniques.
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| 15. |
- Harang, Valérie, et al.
(author)
-
Microemulsion electrokinetic chromatography of drugs varying in charge and hydrophobicity : I. Impact of parameters on separation performance evaluated by multiple linear regression models
- 2004
-
In: Electrophoresis. - : Wiley. - 0173-0835 .- 1522-2683. ; 25:1, s. 80-93
-
Journal article (peer-reviewed)abstract
- The separation of anionic, cationic and neutral drugs in microemulsion electrokinetic chromatography (MEEKC) was studied with a statistical experimental design. The concentration of sodium dodecyl sulfate (SDS, surfactant), 1-butanol (co-surfactant) and borate buffer and the factors Brij 35 (surfactant), 2-propanol (organic solvent) and cassette temperature were varied simultaneously, while the parameters pH (9.2), the concentration of octane (oil, 0.8% w/w), the voltage (10 kV) and the dimension of the fused-silica capillary, were kept constant. Eight different model substances were chosen with different hydrophobicities. Two of the analytes were positively charged, two were negatively charged, and the remaining four were neutral or close to neutral at the pH explored. The importance of each parameter on the separation window, the plate height and the retention factor for each of the analytes was studied by means of multiple linear regression (MLR) models. A new response was evaluated for anions, the quotient between the effective mobility in the microemulsion and the effective mobility in the corresponding buffer. Factors affecting selectivity changes were also explored, and it was found that SDS and 2-propanol had the largest effect on selectivity.
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| 16. |
- Harang, Valérie, et al.
(author)
-
Microemulsion electrokinetic chromatography of drugs varying in charge and hydrophobicity : II. Strategies for optimisation of separation
- 2004
-
In: Electrophoresis. - : Wiley. - 0173-0835 .- 1522-2683. ; 25:12, s. 1792-1809
-
Journal article (peer-reviewed)abstract
- The separation of anionic, cationic, and neutral drugs in microemulsion electrokinetic chromatography (MEEKC) was studied. The concentration of sodium dodecyl sulfate (SDS; surfactant) and 2-propanol (organic solvent) was varied in a three-level full factorial design. 29 different model substances were chosen with different hydrophobicities and charges (neutral, positive, and negative). The models were calculated by means of multiple linear regression (MLR). The compounds were divided into five different subgroups, and different strategies for optimization of the separation within each group were investigated. The optimization was done by maximizing the selectivity using response surface plots in MODDE, by calculation of different chromatographic functions, and by using the software DryLab. For all the different groups, MODDE, almost all chromatographic functions and DryLab gave approximately the same settings of the factors for optimum separation. Attempts were made to fit descriptors of the compounds to the retention data from the three-level full factorial design by means of partial least squares projection to latent structures (PLS). Between 86 and 89% of all predictions of migration times were acceptable (80-120% of the observed value).
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| 17. |
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| 18. |
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| 19. |
- Idborg, Helena, et al.
(author)
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Metabolic fingerprinting of rat urine by LC/MS. : Part1. Analysis by hydrophilic interaction liquid chromatography-electrospray ionization mass spectrometry
- 2005
-
In: Journal of Chromatography B. - : Elsevier BV. - 1387-2273 .- 1878-5603 .- 1570-0232 .- 1873-376X. ; 828:1-2, s. 9-13
-
Journal article (peer-reviewed)abstract
- Complex biological samples, such as urine, contain a very large number of endogenous metabolites reflecting the metabolic state of an organism. Metabolite patterns can provide a comprehensive signature of the physiological state of an organism as well as insights into specific biochemical processes. Although the metabolites excreted in urine are commonly highly polar, the samples are generally analyzed using reversed-phase liquid chromatography mass spectrometry (RP-LC/MS). In Part I of this work, a method for detecting highly polar metabolites by hydrophilic interaction liquid chromatography-electrospray ionization mass spectrometry (HILIC/ESI-MS) is described as a complement to RP-LC/ESI-MS. In addition, in an accompanying paper (Part 2), different multivariate approaches to extracting information from the resulting complex data are described to enable metabolic fingerprints to be obtained. The coverage of the method for the screening of as many metabolites as possible is highly improved by analyzing the urine samples using both a C-18 column and a ZIC (R)-HILIC column. The latter was found to be a good alternative when analyzing highly polar compounds, e.g., hydroxyproline and creatinine, to columns typically used for reversed-phase liquid chromatography. (c) 2005 Elsevier B.V. All rights reserved.
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| 20. |
- Idborg, Helena, et al.
(author)
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Metabolic fingerprinting of rat urine by LC/MS. : Part 2. Data pretreatment methods for handling of complex data
- 2005
-
In: Journal of Chromatography B. - : Elsevier BV. - 1387-2273 .- 1878-5603 .- 1570-0232. ; 828:1-2, s. 14-20
-
Journal article (peer-reviewed)abstract
- Metabolic fingerprinting of biofluids like urine is a useful technique for detecting differences between individuals. With this approach, it might be possible to classify samples according to their biological relevance. In Part I of this work a method for the comprehensive screening of metabolites was described [H. Idborg, L. Zamani, P-O. Edlund, I. Schuppe-Koistinen, S.P. Jacobsson, Part 1, J. Chromatogr. B 828 (2005) 9], using two different liquid chromatography (LC) column set-ups and detection by electrospray ionization mass spectrometry (ESI-MS). Data pretreatment of the resulting data described in [H. Idborg, L. Zamani, P-O. Edlund, 1. Schuppe-Koistinen, S.P. Jacobsson, Part 1, J. Chromatogr. B 828 (2005) 9] is needed to reduce the complexity of the data and to obtain useful metabolic fingerprints. Three different approaches, i.e., reduced dimensionality (RD), MarkerLynx (TM), and MS Resolver (TM), were compared for the extraction of information. The pretreated data were then subjected to multivariate data analysis by partial least squares discriminant analysis (PLS-DA) for classification. By combining two different chromatographic procedures and data analysis, the detection of metabolites was enhanced as well as the finding of metabolic fingerprints that govern classification. Additional potential biomarkers or xenobiotic metabolites were detected in the fraction containing highly polar compounds that are normally discarded when using reversed-phase liquid chromatography.
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| 21. |
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| 22. |
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| 23. |
- Jacobsson, Sven P.
(author)
-
Cold trapping and reinjection techniques for gas chromatography-mass spectrometry
- 1984
-
Doctoral thesis (other academic/artistic)abstract
- This thesis describes the use of cold trapping and reinjection techniques in combination with gas chromatography-mass spectrometry. A summary of different cold trap/ reinjection systems is presented. The merits of the different techniques are discussed with emphasis on concepts and parameters which have been less extensively covered in the included papers.- Cold traps connected via a six-port rotary valve to a packed column gas chromatograph-mass spectrometer have been used to analyse the contents of a glass sampler. In addition, the thermo-oxidative degradation products of polyethylene and polypropylene have been studied by this technique.- Parameters of importance using a cold trap attached to a rotary valve for analysis with capillary columns are described. The cold trap/rotary valve/reinjection system has been applied to the analysis of thermolysis products of polychlorinated alkanes.- A cryogenic enrichment/reinjection technique based on pneumatically controlled flow switching (Deans switching) is also described. Analysis of volatiles in some technical polymers by dynamic headspace, capillary column gas chromatography and mass spectrometry is described.
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| 24. |
- Kölhed, Malin, 1977-
(author)
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Novel on-line mid infrared detection strategies in capillary electrophoretic systems
- 2005
-
Doctoral thesis (other academic/artistic)abstract
- Infrared absorption spectra can provide analytically useful information on a large variety of compounds, ranging from small ions to large biological molecules. In fact, all analytes that possess a dipole moment that changes during vibration are infrared-active. The infrared (IR) spectrum can be subdivided into far-, mid- and near- regions. The focus of attention in this thesis is the mid-IR region, in which the fundamental vibrations of most organic compounds are located, thus providing scope for positive structural identification. However, while such near-ubiquitous signals can be very useful for monitoring simple molecules in simple systems, they can be increasingly disadvantageous as the number of analytes and/or the complexity of the sample matrix increases. Thus, hyphenation to a separation system prior to detection is desirable. Paper I appended to this thesis presents (for the first time) the on-line hyphenation between Fourier transform infrared spectroscopy, FTIR, and capillary zone electrophoresis, CZE. CZE is a highly efficient separation technique that separates ionic analytes with respect to their charge-to-size ratio. It is most commonly performed in aqueous buffers in fused silica capillaries. Since these capillaries absorb virtually all infrared light an IR-transparent flow cell had to be developed. In further studies (Paper II) the applicability of CZE is expanded to include neutral analytes by the addition of micelles to the buffer, and micellar electrokinetic chromatography, MEKC, was successfully hyphenated to FTIR for the first time. Paper III describes an application of the on-line CZE-FTIR technique in which non-UV-absorbing analytes in a complex matrix were separated, identified and quantified in one run.Measuring aqueous solutions in the mid-IR region is not straightforward since water absorbs intensely in this region, sometimes completely, leaving no transmitted, detectable light. For this reason, quantum cascade lasers are interesting. These lasers represent a new type of mid-IR semiconducting lasers with high output power due to their ingenious design. The laser action lies within one conduction band (intersubband) and can be tailored to emit light in the entire mid-IR region using the same semiconducting material. To investigate their potential to increase the optical path length in aqueous solutions, these lasers were used with an aqueous flow system (Paper IV), and the experience gained in these experiments enabled hyphenation of such lasers to a CZE system (Paper V).
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| 25. |
- Lee, James J, et al.
(author)
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Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.
- 2018
-
In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 50:8, s. 1112-1121
-
Journal article (peer-reviewed)abstract
- Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1million individuals and identify 1,271independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.
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| 26. |
- Okbay, Aysu, et al.
(author)
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Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals.
- 2022
-
In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:4, s. 437-449
-
Journal article (peer-reviewed)abstract
- We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12-16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI's magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57.
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| 27. |
- Röbeck, Pontus, et al.
(author)
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Multiplex protein analysis and ensemble machine learning methods of fine needle aspirates from prostate cancer patients reveal potential diagnostic signatures associated with tumour grade
- 2023
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In: Cytopathology. - : Wiley. - 0956-5507 .- 1365-2303. ; 34:4, s. 286-294
-
Journal article (peer-reviewed)abstract
- Background: Improved molecular diagnosis is needed in prostate cancer (PC). Fine needle aspiration (FNA) is a minimally invasive biopsy technique, less traumatic compared to core needle biopsy, and could be useful for diagnosis of PC. Molecular biomarkers (BMs) in FNA-samples can be assessed for prediction, eg of immunotherapy efficacy before treatment as well as at treatment decision time points during disease progression.Methods: In the present pilot study, the expression levels of 151 BM proteins were analysed by proximity extension assay in FNA-samples from 16 patients, including benign prostate lesions (n = 3) and cancers (n = 13). An ensemble data analysis strategy was applied using several machine learning models.Results: Twelve potentially predictive BM proteins correlating with International Society of Urological Pathology grade groups were identified, among them vimentin, tissue factor pathway inhibitor 2, and integrin beta-5. The validity of the results was supported by network analysis that showed functional associations between most of the identified putative BMs. We also showed that multiple immune checkpoint targets can be assessed (eg PD-L1, CD137, and Galectin-9), which may support the selection of immunotherapy in advanced PC. Results are promising but need further validation in a larger cohort.Conclusions: Our pilot study represents a “proof of concept” and shows that multiplex profiling of potential diagnostic and predictive BM proteins is feasible on tumour material obtained by FNA sampling of prostate cancer. Moreover, our results demonstrate that an ensemble data analysis strategy may facilitate the identification of BM signatures in pilot studies when the patient cohort is limited.
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| 28. |
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| 29. |
- Samskog, Jenny, et al.
(author)
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Miniaturized on-line proteolysis-packed capillary liquid chromatography-mass spectrometry for peptide mapping of lactate dehydrogenase
- 2003
-
In: Journal of Chromatography A. - 0021-9673. ; 998:1/2, s. 83-91
-
Journal article (peer-reviewed)abstract
- In this study, methodology was developed for on-line and miniaturized enzymatic digestion with liquid chromatographic (LC) separation and mass spectrometric (MS) detection. A packed capillary LC–MS system was combined with on-line trypsin cleavage of a model protein, lactate dehydrogenase, to provide an efficient system for peptide mapping. The protein was injected onto an enzymatic capillary reactor and the resulting peptides were efficiently trapped on a capillary trapping column. Different trapping columns were evaluated to achieve a high binding capacity for the peptides generated in the enzyme reactor. The peptides were further eluted from the pre-column and separated on an analytical capillary column by a buffer more suitable for the following an electrospray ionisation (ESI) MS process. An important aspect of the on-line approach was the desalting of peptides performed in the trapping column to avoid detrimental signal suppression in the ESI process. The developed on-line system was finally compared to a classical digestion in solution, with reference to peptide sequence coverage and sensitivity. It was shown that the on-line system gave more than 100% higher peptide sequence coverage than traditional digestion methods.
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| 30. |
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| 31. |
- Stolt, Ragnar, et al.
(author)
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Second-Order Peak Detection for Multicomponent High-Resolution LC/MS Data
- 2006
-
In: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 78:4, s. 975-83
-
Journal article (peer-reviewed)abstract
- The first step when analyzing multicomponent LC/MS data from complex samples such as biofluid metabolic profiles is to separate the data into information and noise via, for example, peak detection. Due to the complex nature of this type of data, with problems such as alternating backgrounds and differing peak shapes, this can be a very complex task. This paper presents and evaluates a two-dimensional peak detection algorithm based on raw vector-represented LC/MS data. The algorithm exploits the fact that in high-resolution centroid data chromatographic peaks emerge flanked with data voids in the corresponding mass axis. According to the proposed method, only 4‰ of the total amount of data from a urine sample is defined as chromatographic peaks; however, 94% of the raw data variance is captured within these peaks. Compared to bucketed data, results show that essentially the same features that an experienced analyst would define as peaks can automatically be extracted with a minimum of noise and background. The method is simple and requires a priori knowledge of only the minimum chromatographic peak widtha system-dependent parameter that is easily assessed. Additional meta parameters are estimated from the data themselves. The result is well-defined chromatographic peaks that are consistently arranged in a matrix at their corresponding m/z values. In the context of automated analysis, the method thus provides an alternative to the traditional approach of bucketing the data followed by denoising and/or one-dimensional peak detection. The software implementation of the proposed algorithm is available at http://www.anchem.su.se/peakd as compiled code for Matlab.
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| 32. |
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| 33. |
- Tu, Yaoquan, et al.
(author)
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Efficient ab initio tight-binding-like method for electronic structure calculations
- 2006
-
In: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X. ; 74:20, s. 205104-
-
Journal article (peer-reviewed)abstract
- A reliable and highly efficient ab initio tight-binding-like electronic structure calculation method is developed. The method starts from a similar approach outlined by Horsfield [Phys. Rev. B 56, 6594 (1997)], but in this work, the integral evaluations for the exchange-correlation matrix elements are achieved with reasonable accuracy by higher-order many-center expansions. All the integrals are obtained by the use of look-up tables and the efficiency of the calculation is further improved by optimizing the way to choose the integrals in the look-up tables. Calculations on molecular properties (such as equilibrium geometries, dipole moments, and the reaction energies for hydrogenation reactions for a series of molecules containing H, C, N, and O atoms) show that the method thus developed can be used as a general tool for the electronic structure calculations.
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| 34. |
- Wiberg, Kent, et al.
(author)
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Determination of the content and identity of lidocaine soluions with UV-visible spectroscopy and multivariate calibration
- 2001
-
In: The Analyst. - : Royal Society of Chemistry (RSC). - 0003-2654 .- 1364-5528. ; 126:7, s. 1142-1148
-
Journal article (peer-reviewed)abstract
- A method is proposed for the determination of the content and identity of the active compound in pharmaceutical solutions by means of ultraviolet-visible (UV–Vis) spectroscopy, orthogonal signal correction (OSC) and multivariate calibration with soft independent modelling of class analogy (SIMCA) classification and partial least squares (PLS) regression. The content was determined with PLS regression and the identity with PLS regression and SIMCA classification. The method was tested on the local anaesthetic compound lidocaine. For the validation, external test sets of both manufactured sample solutions and samples from a stability study were used. For comparison with this new method, liquid chromatography was used as a reference method. The results show that in respect of accuracy, precision and repeatability, the new method is comparable to the reference method. The main advantage over liquid chromatography is the much shorter time of analysis and the simpler analytical procedure. An estimate of the analysis time saved with the proposed method compared with using liquid chromatography, together with practical considerations, is given.
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| 35. |
- Wiberg, Kent, et al.
(author)
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Parallel factor analysis of HPLC-DAD data for binary mixtures of lidocaine and prilocaine with different levels of separation
- 2004
-
In: Analytica Chimica Acta. - : Elsevier BV. - 0003-2670 .- 1873-4324. ; 514:2, s. 203-209
-
Journal article (peer-reviewed)abstract
- A set of 17 samples containing a constant amount of lidocaine (667 muM) and a decreasing amount of prilocaine (667-0.3 muM) was analysed by LC-DAD at three different levels of separation, followed by parallel factor analysis (PARAFAC) of the data obtained. In Case 1 no column was connected, the chromatographic resolution (R-s) therefore being zero, while Cases 2 and 3 had partly separated peaks (R-s = 0.7 and 1.0). The results showed that in Case 1, analysed without any separation, the PARAFAC decomposition with a model consisting of two components gave a good estimate of the spectral and concentration profiles of the two compounds. In Cases 2 and 3, the use of PARAFAC models with two components resolved the underlying chromatographic, spectral and concentration profiles. The loadings related to the concentration profile of prilocaine were used for regression and prediction of the prilocaine content. The results showed that prediction of prilocaine content was possible with satisfactory prediction (RMSEP < 0.01). This study shows that PARAFAC is a powerful technique for resolving partly separated peaks into their pure chromatographic, spectral and concentration profiles, even with completely overlapping spectra and the absence or very low levels of separation.
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| 36. |
- Wiberg, Kent, et al.
(author)
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Peak purity determination with principal component analysis of high-performance liquid chromatography-diode array detection data
- 2004
-
In: Journal of Chromatography A. - : Elsevier BV. - 0021-9673 .- 1873-3778. ; 1029:1-2, s. 13-20
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Journal article (peer-reviewed)abstract
- A method is proposed for the determination of chromatographic peak purity by means of principal component analysis (PCA) of high-performance liquid chromatography with diode array detection (HPLC–DAD) data. The method is exemplified with analysis of binary mixtures of lidocaine and prilocaine with different levels of separation. Lidocaine and prilocaine have very similar spectra and the chromatograms used had substantial peak overlap. The samples analysed contained a constant amount of lidocaine and a minor amount of prilocaine (0.02–2 conc.%) and hence the focus was on determining the purity of the lidocaine peak in the presence of much smaller levels of prilocaine. The peak purity determination was made by examination of relative observation residuals, scores and loadings from the PCA decomposition of DAD data over a chromatographic peak. As a reference method, the functions for peak purity analysis in the chromatographic data system used (Chromeleon) were applied. The PCA method showed good results at the same level as the detection limit of baseline-separated prilocaine, outperforming the methods in Chromeleon by a factor of ten. There is a discussion of the interpretation of the result, with some comparisons with evolving factor analysis (EFA). The main advantage of the PCA method for determination of peak purity over methods like EFA lies in its simplicity, short time of calculation and ease of use.
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| 37. |
- Wiberg, Kent, et al.
(author)
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Rapid determination of lidocaine solutions with non-column chromatographic diode array UV spectroscopy and multivariate calibration
- 2003
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In: Journal of Pharmaceutical and Biomedical Analysis. - 0731-7085 .- 1873-264X. ; 30:5, s. 1575-1586
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Journal article (peer-reviewed)abstract
- A new method for the rapid determination of pharmaceutical solutions is proposed. A conventional HPLC system with a Diode Array Detector (DAD) was used with no chromatographic column connected. As eluent, purified water (Milli Q) was used. The pump and autosampler of the HPLC system were mainly utilised as an automatic and convenient way of introducing the sample into the DAD. The method was tested on the local anaesthetic compound lidocaine. The UV spectrum (245–290 nm) from the samples analysed in the detector was used for multivariate calibration for the determination of lidocaine solutions. The content was determined with PLS regression. The effect on the predictive ability of three factors: flow, data-collection rate and rise time as well as two ways of exporting a representative UV spectrum from the DAD file collected was investigated by means of an experimental design comprising 11 experiments. For each experiment, 14 solutions containing a known content of lidocaine were analysed (0.02–0.2 mg ml−1). From these 14 samples two calibration sets and two test sets were made and as the response in the experimental design the Root Mean Square Error of Prediction (RMSEP) values from the predictions of the two test sets were used. When the factor setting giving the lowest RMSEP was found, this setting was used when analysing a new calibration set of 12 lidocaine samples (0.1–0.2 mg ml−1). This calibration model was validated by two external test sets, A and B, analysed on separate occasions for the evaluation of repeatability (test set A) and determination over time (test set B). For comparison, the reference method, liquid chromatography, was also used for analysis of the ten samples in test set B. This comparison of the two methods was done twice on different occasions. The results show that in respect of accuracy, precision and repeatability the new method is comparable to the reference method. The main advantages compared with liquid chromatography are the much shorter time of analysis (<30 s) as well as the automatic and simple analytical procedure and the low consumption of organic solvents.
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| 38. |
- Wiberg, Kent, et al.
(author)
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Simultaneous determination of albumin and immunoglobulin G with fluorescence spectroscopy and multivariate calibration
- 2004
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In: Talanta. - : Elsevier BV. - 0039-9140 .- 1873-3573. ; 62:3, s. 567-574
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Journal article (peer-reviewed)abstract
- A method is proposed for the simultaneous determination of albumin and immunoglobulin G (IgG1) with fluorescence spectroscopy and multivariate calibration with partial least squares regression (PLS). The influence of some instrumental parameters were investigated with two experimental designs comprising 19 and 11 experiments, respectively. The investigated parameters were excitation and emission slit, detection voltage and scan rate. When a suitable instrumental setting had been found, a minor calibration and test set were analysed and evaluated. Thereafter, a larger calibration of albumin and IgG1 was made out of 26 samples (0–42 μg ml−1 albumin and 0–12.7 μg ml−1 IgG1). This calibration was validated with a test set consisting of 14 samples in the same concentration range. The precision of the method was estimated by analysing two test set samples for six times each. The scan modes tested were emission scan and synchronous scan Δ60 nm. The results showed that the method could be used for determination of albumin and IgG1 (albumin, root mean square error of prediction (RMSEP) <2, relative standard error of prediction (RSEP) <6% and IgG1, RMSEP <1, RSEP <8%) in spite of the overlapping fluorescence of the two compounds. The estimated precision was relative standard deviation (R.S.D.) <1.7%. The method was finally applied for the analysis of some sample fractions from an albumin standard used in affinity chromatography.
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| 39. |
- Wiberg, Kent, et al.
(author)
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Use of control sample for estimation of prediction error in multivariate determination of lidocaine solutions with non-column chromatographic diode array UV spectroscopy
- 2003
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In: Journal of Pharmaceutical and Biomedical Analysis. - 0731-7085 .- 1873-264X. ; 33:5, s. 859-869
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Journal article (peer-reviewed)abstract
- The aim of this study was to investigate the ability of a control sample, of known content and identity, to diagnose and correct errors in the predictions when the same multivariate calibration model was used for analysis of new samples over time. A calibration set consisting of 16 samples with a known content of lidocaine was analysed and two external test sets, A and B, were used for the validation. Test set A contained 15 samples with different concentrations of lidocaine and test set B contained three samples with different lidocaine content, which were analysed six times in order to obtain a measure of repeatability. The multivariate calibration was done with PLS regression on UV spectra collected between 245 and 290 nm. A representative UV spectrum was exported from the collected DAD files by two methods, average spectrum over the whole file and average spectrum over the sample plug. Test set A was analysed further on another three occasions together with a control sample. The results showed that the control sample could be used to give a diagnosis and estimate of the prediction error. Moreover, the measured prediction error of the control sample could also be used to correct the predictions, thereby reducing the prediction error. Finally, some practical considerations regarding use of the proposed DAD method with a control sample are presented. The procedure suggested could lead to an efficient analytical approach where the same calibration model could be used over time without recalibration, which may be attractive in industrial quality control or screening analysis in pharmaceutical research.
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| 40. |
- Zamani, Leila, et al.
(author)
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Conformational studies of a monoclonal antibody, IgG1, by chemical oxidation: Structural analysis by ultrahigh-pressure LC-electrospray ionization time-of-flight MS and multivariate data analysis
- 2008
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In: Analytical Biochemistry. - : Elsevier BV. - 0003-2697 .- 1096-0309. ; 380:2, s. 155-163
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Journal article (peer-reviewed)abstract
- We describe the development of a method in which protein oxidation by H2O2 followed by ultrahigh-pressure liquid chromatography (UHPLC) coupled with electrospray ionization time-of-flight mass spectrometry (ESI-ToFMS) and multivariate analysis are used to detect alterations in conformational states of proteins. In the study reported here, an IgG1 monoclonal antibody in native and denatured conformational states was oxidized by treatment with hydrogen peroxide. Peptide fragments generated by tryptic digestion were then analyzed by UHPLC-ESI-ToFMS. After reducing noise and extracting peaks from the LC-MS data using MzExplorer, software developed in-house and based on Matlab, we were able to distinguish peptides arising from the native and denatured states of the oxidized protein by principal component analysis. Peptides containing residues, which are inclined to undergo oxidation, such as methionine, are founded to be particularly important in this approach. We believe that the methodology could facilitate attempts to characterize the conformational states of recombinant monoclonal antibodies and other proteins.
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| 41. |
- Zamani, Leila, et al.
(author)
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Discrimination among IgG1-Κ monoclonal antibodies produced by two cell lines using charge state distributions in nanoESI-TOF mass spectra
- 2009
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In: Journal of the American Society for Mass Spectrometry. - : American Chemical Society (ACS). - 1044-0305 .- 1879-1123. ; 20:6, s. 1030-1036
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Journal article (peer-reviewed)abstract
- Charge state distributions (CSDs) of proteins in nanoESI mass spectra are affected by the instrumental settings and experimental conditions, in addition to the conformations of the proteins in the analyzed solutions. In the presented study, instrumental and experimental parameters-the desolvation gas flow rate, temperature, pH, buffer (ammonium acetate), and organic modifier (methanol) concentrations-were optimized according to a reduced central composite face experimental design to maximize the separation of CSDs of monoclonal IgG1-kappa antibodies produced by two production systems (CHO and GS-NS0 cell lines). Principal component analysis and Fisher linear discriminant analysis were then used to reduce the dimensions of the acquired dataset and quantify the separation of the protein classes, respectively. The results show that the IgG1-kappa molecules produced by the two production systems can be clearly distinguished using the described approach, which could be readily applied to other proteins and production systems.
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| 42. |
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| 43. |
- Zamani, Leila, 1971-
(author)
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Methods for structural studies of an antibody, screening metabolites in rat urine and analysis of spent cell cultivation media using LC/ESI-MS and chemometrics
- 2009
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Doctoral thesis (other academic/artistic)abstract
- This thesis describes bioanalytical methods for generating fingerprints of biological systems for extracting relevant information with (protein) drugs in focus. Similarities and differences between samples can reveal the hidden relevant information, which can be used to optimize the production and facilitate the quality control of such protein drugs during their development and manufacture. Metabolic fingerprinting and multivariate data analysis (MVDA) can also facilitate early diagnosis of diseases and the effects and toxicity of drugs. Currently, several protein drugs are available on the global market. Nevertheless, despite, the success of such biotherapeutics significant challenges remain to be overcome in maintaining their stability and efficacity throughout their production cycle and long-term storage. The native structure and functional activity of therapeutic proteins is affected by many variables from production to delivery, incl. variables assoc. with conditions in bioreactors, purification, storage and delivery. Thus, part of the work underlying this thesis focused on structural analysis of a protein drug using chemical labeling, peptide mapping, and evaluation of the charge state distributions of the whole protein generated by ESI. The other part focuses on non-targeted metabolomics with a view to optimizing the cell cultivation process and assessment of the drug’s toxicity. A combination of appropriate analytical methods and MVDA is needed to find markers that can facilitate optimization of the cultivation system and expression of the target proteins in early stages of process development. Rapid methods for characterizing the protein drugs in different stages of the process are also required for quality control. In order to obtain high quality fingerprints analytical separation techniques with high resolution (such as HPLC or UHPLC) and sensitive analytical detection techniques (such as ESI, quadrupole or TOF MS) have been used, singly or in combination.
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| 44. |
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| 45. |
- Åberg, K. Magnus, et al.
(author)
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Extensions to peak alignment using reduced set mapping and classification of LC-UV data from peptide mapping
- 2005
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In: Journal of Chemometrics. - : Wiley InterScience. - 0886-9383 .- 1099-128X. ; 18:10, s. 465-473
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Journal article (peer-reviewed)abstract
- Peak alignment using reduced set mapping (PARS) is extended with a new baseline approximation and a new dendrogram alignment scheme, which is designed to avoid the issue of selecting a target chromatogram for the alignment. Two data sets with LC/UV data are studied and it is shown that peak alignment with PARS increases the class separation substantially in the principal component score space. The results indicate that it is possible to use PARS for calibration transfer of multivariate models of chromatographic data.
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| 46. |
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| 47. |
- Åberg, K. Magnus, 1976-
(author)
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Variance Reduction in Analytical Chemistry : New Numerical Methods in Chemometrics and Molecular Simulation
- 2004
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Doctoral thesis (other academic/artistic)abstract
- This thesis is based on five papers addressing variance reduction in different ways. The papers have in common that they all present new numerical methods.Paper I investigates quantitative structure-retention relationships from an image processing perspective, using an artificial neural network to preprocess three-dimensional structural descriptions of the studied steroid molecules.Paper II presents a new method for computing free energies. Free energy is the quantity that determines chemical equilibria and partition coefficients. The proposed method may be used for estimating, e.g., chromatographic retention without performing experiments.Two papers (III and IV) deal with correcting deviations from bilinearity by so-called peak alignment. Bilinearity is a theoretical assumption about the distribution of instrumental data that is often violated by measured data. Deviations from bilinearity lead to increased variance, both in the data and in inferences from the data, unless invariance to the deviations is built into the model, e.g., by the use of the method proposed in paper III and extended in paper IV.Paper V addresses a generic problem in classification; namely, how to measure the goodness of different data representations, so that the best classifier may be constructed. Variance reduction is one of the pillars on which analytical chemistry rests. This thesis considers two aspects on variance reduction: before and after experiments are performed. Before experimenting, theoretical predictions of experimental outcomes may be used to direct which experiments to perform, and how to perform them (papers I and II). After experiments are performed, the variance of inferences from the measured data are affected by the method of data analysis (papers III-V).
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