Assessing the statistical validity of proteomics based biomarkers

A strategy is presented for the statistical validation of discrimination models in proteomics studies. Several existing tools are combined to form a solid statistical basis for biomarker discovery that should precede a biochemical validation of any biomarker. These tools consist of permutation tests, single and double cross-validation. The cross-validation steps can simply be combined with a new variable selection method, called rank products. The strategy is especially suited for the low-samples-to-variables-ratio (undersampling) case, as is often encountered in proteomics and metabolomics studies. As a classification method, principal component discriminant analysis is used; however, the methodology can be used with any classifier. A dataset containing serum samples from Gaucher patients and healthy controls serves as a test case. Double cross-validation shows that the sensitivity of the model is 89% and the specificity 90%. Potential putative biomarkers are identified using the novel variable selection method. Results from permutation tests support the choice of double cross-validation as the tool for determining error rates when the modelling procedure involves a tuneable parameter. This shows that even cross-validation does not guarantee unbiased results. The validation of discrimination models with a combination of permutation tests and double cross-validation helps to avoid erroneous results which may result from the undersampling.     

A decade of microfluidic analysis coupled with electrospray mass spectrometry: an overview

This review presents a thorough overview covering the period 1997-2006 of microfluidic chips coupled to mass spectrometry through an electrospray interface. The different types of fabrication processes and materials used to fabricate these chips throughout this period are discussed. Three 'eras' of interfaces are clearly distinguished. The earliest approach involves spraying from the edge of a chip, while later devices either incorporate a standard fused-silica emitter inserted into the device or fully integrated emitters formed during chip fabrication. A summary of microfluidic-electrospray devices for performing separations and sample pretreatment steps before sample introduction into the mass spectrometer is also presented.     

Forecasting demand for single-period products: A case study in the apparel industry

The problem considered is that of forecasting demand for single-period products before the period starts. We study this problem for the case of a mail order apparel company that needs to order its products pre-season. The lack of historical demand data implies that other sources of data are needed. Advance order data can be obtained by allowing a selected group of customers to pre-order at a discount from a preview catalogue. Judgments can be obtained from purchase managers or other company experts. In this paper, we compare several existing and new forecasting methods for both sources of data. The methods are generic and can be used in any single-period problem in the apparel or fashion industries. Among the pre-order based methods, a novel ‘top-flop’ approach provides promising results. For a small group of products from the case company, expert judgment methods perform better than the methods based on advance demand information. The comparative results are obviously restricted to the specific case study, and additional testing is required to determine whether they are valid in general.     

Finite-difference method without spurious solutions for thehybrid-mode analysis of diffused channel waveguides

Diffused dielectric channel waveguides with an arbitrarily varying refractive index profile in the cross-sectional plane are analyzed with a rigorous finite-difference method. The method is formulated in terms of the wave equation for the transverse components of the magnetic field. This leads to an eigenvalue problem where the nonphysical, spurious modes do not appear. The analysis includes the complete set of hybrid modes, takes mode-conversion effects and complex waves into account, and allows the immediate inclusion of large index difference levels as well as the two-dimensional continuously varying index profile function without the usual staircase approximation. As an example, dispersion characteristics are calculated for structures suitable for millimeter-wave and optical integrated circuits, such as channel waveguides with refractive index variations having stepped, linear, Gaussian, and exponential function profiles. The theory is verified by comparison with results available from other rigorous methods     

The hydrosphere State (hydros) Satellite mission: an Earth system pathfinder for global mapping of soil moisture and land freeze/thaw

The Hydrosphere State Mission (Hydros) is a pathfinder mission in the National Aeronautics and Space Administration (NASA) Earth System Science Pathfinder Program (ESSP). The objective of the mission is to provide exploratory global measurements of the earth's soil moisture at 10-km resolution with two- to three-days revisit and land-surface freeze/thaw conditions at 3-km resolution with one- to two-days revisit. The mission builds on the heritage of ground-based and airborne passive and active low-frequency microwave measurements that have demonstrated and validated the effectiveness of the measurements and associated algorithms for estimating the amount and phase (frozen or thawed) of surface soil moisture. The mission data will enable advances in weather and climate prediction and in mapping processes that link the water, energy, and carbon cycles. The Hydros instrument is a combined radar and radiometer system operating at 1.26 GHz (with VV, HH, and HV polarizations) and 1.41 GHz (with H, V, and U polarizations), respectively. The radar and the radiometer share the aperture of a 6-m antenna with a look-angle of 39/spl deg/ with respect to nadir. The lightweight deployable mesh antenna is rotated at 14.6 rpm to provide a constant look-angle scan across a swath width of 1000 km. The wide swath provides global coverage that meet the revisit requirements. The radiometer measurements allow retrieval of soil moisture in diverse (nonforested) landscapes with a resolution of 40 km. The radar measurements allow the retrieval of soil moisture at relatively high resolution (3 km). The mission includes combined radar/radiometer data products that will use the synergy of the two sensors to deliver enhanced-quality 10-km resolution soil moisture estimates. In this paper, the science requirements and their traceability to the instrument design are outlined. A review of the underlying measurement physics and key instrument performance parameters are also presented.     

The effect of storage temperature on interactions between dehydrated sugars and phosphatidylcholine

We studied the effects of storage temperature on the stability of dehydrated POPC (1-palmitoyl-2-oleoyl-phosphatidylcholine) mixed with sucrose, trehalose, or a sucrose/raffinose mixture. We used DSC to measure the gel-to-fluid phase transition temperature (T _m) of POPC after incubation either below or near the glass transition temperature (T _g) of the sugars in the mixture. Glass formation by the sugars around fluid-phase POPC led to the lowering ofT _m below that of the fully hydrated lipid. Phospholipid phase behavior did not change during storage belowT _g. In some samples stored aboveT _g, trehalose crystallized completely; in these samples, theT _g of POPC increased to that of the partially dehydrated phospholipid. Melting the crystalline sugar re-established its ability to lower POPC'sT _m. We conclude that prevention of complete sugar crystallization was important for stability in the dry state, and that storage belowT _g conferred long-term stability to the dehydrated sugar-lipid mixtures.     

Isomer separation of hyperbranched polyesteramides with gas-phase H/D exchange and a novel MS(n) approach: DoDIP

Two approaches are introduced that provide information about the isomeric composition of hyperbranched polyesteramides. The first approach is based on a novel tandem mass spectrometric (MS(n)) approach that allows the study of different types of isomeric structures by a separation based on their difference in appearance energy. The method is called DoDIP: dissociation of depleted ion populations. A first MS/MS step is used to fragment isomers with relatively low appearance energy. The isomers with higher appearance energy are fragmented in a second MS/MS step of higher energy. The second approach is based on gas-phase H/D exchange experiments that result in a bimodal isotopic distribution for oligomers X(n)D(n+1) of which one distribution corresponds to a type of isomeric structure that exhibits H/D exchange behaviour and the other to an isomeric structure that does not exhibit H/D exchange behaviour. X is a difunctional anhydride of phthalic acid (P), 1,2-cyclohexanedicarboxylic acid (C), succinic acid (S) or glutaric acid (G). D in X(n)D(n+1) is a trifunctional diisopropanolamine and n the degree of polymerization. The type of isomeric structure that does not exhibit H/D exchange behaviour has a non-alternating monomer sequence that contains an amine bond with a relatively high proton affinity. The other isomeric structure that does exhibit H/D exchange behaviour has an alternating monomer sequence containing only amide and ester bonds with relatively low proton affinity. Oligomer structures were confirmed with additional MS(2) experiments after H/D exchange. H/D exchange experiments on the fragments obtained after MS(2) of the parent ion show that next to previously postulated mechanisms for the cleavage of the ester and amide bond another reaction pathway must be operational. A new mechanism is introduced to explain the H/D exchange behaviour of the fragments that requires a cleavage of the amide bonds only. Two types of fragments are formed by this mechanism. One type is protonated due to the cleavage of the amide bond whereas the other type has an oxazolonium ion structure due to the loss of an additional H(2)O.