Alan Heckert

Novel Extreme Value Estimation Procedures: Application to Extreme Wind Data

The past two decades have seen the development of a large body of extreme value theory based on the application of the Generalized Pareto Distribution (GPD) to the excess of the extreme variate over a fixed threshold. For sufficiently large values of the extreme variates, the GPD with tail length parameters c > 0 and c < 0 is equivalent, respectively, to the Type II (Frechet) and Type III (reverse Weibull) distribution of the largest values. The Type I (Gumbel) distribution is equivalent to the limit of the GPD as c→0. Owing to these equivalences, the GPD can be used to model extreme data obtained by either the ’peaks over threshold’ approach or the epochal approach.

Harmonizing lipidomics: NIST interlaboratory comparison exercise for lipidomics using SRM 1950–Metabolites in Frozen Human Plasma

As the lipidomics field continues to advance, self-evaluation within the community is critical. Here, we performed an interlaboratory comparison exercise for lipidomics using Standard Reference Material (SRM) 1950–Metabolites in Frozen Human Plasma, a commercially available reference material. The interlaboratory study comprised 31 diverse laboratories, with each laboratory using a different lipidomics workflow. A total of 1,527 unique lipids were measured across all laboratories and consensus location estimates and associated uncertainties were determined for 339 of these lipids measured at the sum composition level by five or more participating laboratories. These evaluated lipids detected in SRM 1950 serve as community-wide benchmarks for intra- and interlaboratory quality control and method validation. These analyses were performed using nonstandardized laboratory-independent workflows. The consensus locations were also compared with a previous examination of SRM 1950 by the LIPID MAPS consortium. While the central theme of the interlaboratory study was to provide values to help harmonize lipids, lipid mediators, and precursor measurements across the community, it was also initiated to stimulate a discussion regarding areas in need of improvement.

Improving optical measurement accuracy using multi-technique nested uncertainties

This paper compares and contrasts different combinations of scatterfield and scatterometry optical configurations as well as introduces a new approach to embedding atomic force microscopy (AFM) or other reference metrology results directly in the uncertainty analysis and library-fitting process to reduce parametric uncertainties. We present both simulation results and experimental data demonstrating this new method, which is based on the application of a Bayesian analysis to library-based regression fitting of optical critical dimension (OCD) data. We develop the statistical methods to implement this approach of nested uncertainty analysis and give several examples, which demonstrate reduced uncertainties in the final combined measurements. The approach is also demonstrated through a combined reference metrology application using several independent measurement methods.

Development of orthogonal NISTmAb size heterogeneity control methods

AbstractThe NISTmAb is a monoclonal antibody Reference Material from the National Institute of Standards and Technology; it is a class-representative IgG1κ intended to serve as a pre-competitive platform for harmonization and technology development in the biopharmaceutical industry. The publication series of which this paper is a part describes NIST’s overall control strategy to ensure NISTmAb quality and availability over its lifecycle. In this paper, the development of a control strategy for monitoring NISTmAb size heterogeneity is described. Optimization and qualification of size heterogeneity measurement spanning a broad size range are described, including capillary electrophoresis-sodium dodecyl sulfate (CE-SDS), size exclusion chromatography (SEC), dynamic light scattering (DLS), and flow imaging analysis. This paper is intended to provide relevant details of NIST’s size heterogeneity control strategy to facilitate implementation of the NISTmAb as a test molecule in the end user’s laboratory. Graphical abstractRepresentative size exclusion chromatogram of the NIST monoclonal antibody (NISTmAb). The NISTmAb is a publicly available research tool intended to facilitate advancement of biopharmaceutical analytics. HMW = high molecular weight (trimer and dimer), LMW = low molecular weight (2 fragment peaks). Peak labeled buffer is void volume of the column from L-histidine background buffer.

Analysis of Deamidation Artifacts Induced by Microwave-Assisted Tryptic Digestion of a Monoclonal Antibody

The thorough characterization of biopharmaceuticals is essential for ensuring their quality and safety since many potential variations can cause changes to the properties of a drug that may be detrimental to the patient such as decreased efficacy, shorter half-life or increased immunogenicity. Prior to approval and release, protein-based drugs are subject to a battery of analyses to assess the nature of those parameters that are considered critical quality attributes. In some cases the analytical method used may itself cause modifications that are impossible to distinguish from those induced by the intended test conditions (e.g. storage time/temperature, light exposure) which are used to assess drug stability. It is therefore important to develop and utilize analytical methods which impose as few artifactual modifications as possible. Asparagine deamidation is a common protein modification and it is known to be induced during tryptic digestion. Therefore we examined common tryptic digestion protocols and compared their propensities towards asparagine modification. Since microwave assisted hydrolysis techniques are often used to shorten digestion times and the effect on deamidation is unknown we sought to compare this method against alternate digestion protocols.

Dependence of electron density on Fermi energy in compensated n-type gallium antimonide

The majority electron density as a function of the Fermi energy is calculated in zinc blende, compensated n-type GaSb for donor densities between 1016 and 1019cm−3. The compensation acceptor density is 1016cm−3. These calculations solve the charge neutrality equation self-consistently for a four-band model (three conduction subbands at Γ, L, and X and one equivalent valence band at Γ) of GaSb. Our calculations assume parabolic densities of states and thus do not treat the density-of-states modifications due to high concentrations of dopants, many-body effects, and nonparabolicity of the bands. Even with these assumptions, the results are important for interpreting optical measurements such as Raman scattering measurements that are proposed as a nondestructive method for wafer acceptance tests.

Performance Criteria for Chemical Analysis of Hydraulic Cements by X-Ray Fluorescence Analysis

Bulk oxide determinations from two pairs of ASTM C150/C150M-12 portland cements are used to calculate precision and accuracy values for X-ray fluorescence (XRF) by both the fused glass bead and the pressed powder sample preparation methods. The first pair of cements are ordinary portland cement (OPC) with 45 participants, while the second pair contains ca. 3 % limestone, with 24 labs participating. Each lab provided results from six replicates analyzed in duplicate, covering fifteen analytes, CaO, SiO2, Al2O3, Fe2O3, SO3, MgO, Na2O, K2O, TiO2, P2O5, Mn2O3, SrO, ZnO, Cr2O3, and Cl, with the laboratories roughly split between the two different sample preparations. Chemical data using traditional chemical analyses (the Reference Methods per ASTM C150) from the Cement and Concrete Reference Laboratory (CCRL) proficiency test program were included for comparison to the XRF results. Precision measures for within- and between-laboratory performance are presented as 1σ and 95 % limits (ASTM d2s). Accuracy criteria are based upon a two-sided 95 % prediction interval for the mean of two separate test results, defining the range of values one might expect for each analyte relative to a certified value of a reference material. Comparing to current C114 limits, based upon classical wet chemical analysis, within-lab precision for CaO is larger, wheras SiO2 precision is similar to existing limits. Al2O3 and Fe2O3 precisions are substantially better, whereas for the remaining analytes, the precision is generally similar to ASTM C114 limits. A comparison of the ASTM accuracy criteria shows that CaO accuracy is poorer than the current limit, SO3 is larger, SiO2 and Na2O are similar, while the remaining accuracy limits for XRF are generally better than the ASTM C114 criteria. The powder method shows a positive relative bias for CaO for the cements containing less than 5 % limestone, suggesting a need for more limestone-containing reference materials for powder method calibration for these cements.