Unique and shared systemic biomarkers for emphysema in Alpha-1 Antitrypsin deficiency and chronic obstructive pulmonary disease.

BACKGROUND: Alpha-1 Antitrypsin (AAT) deficiency (AATD), the most common genetic cause of emphysema presents with unexplained phenotypic heterogeneity in affected subjects. Our objectives to identify unique and shared AATD plasma biomarkers with chronic obstructive pulmonary disease (COPD) may explain AATD phenotypic heterogeneity. METHODS: The plasma or serum of 5,924 subjects from four AATD and COPD cohorts were analyzed on SomaScan V4.0 platform. Using multivariable linear regression, inverse variance random-effects meta-analysis, and Least Absolute Shrinkage and Selection Operator (LASSO) regression we tested the association between 4,720 individual proteins or combined in a protein score with emphysema measured by 15th percentile lung density (PD15) or diffusion capacity (DLCO) in distinct AATD genotypes (Pi*ZZ, Pi*SZ, Pi*MZ) and non-AATD, PiMM COPD subjects. AAT SOMAmer accuracy for identifying AATD was tested using receiver operating characteristic curve analysis. FINDINGS: In PiZZ AATD subjects, 2 unique proteins were associated with PD15 and 98 proteins with DLCO. Of those, 68 were also associated with DLCO in COPD also and enriched for three cellular component pathways: insulin-like growth factor, lipid droplet, and myosin complex. PiMZ AATD subjects shared similar proteins associated with DLCO as COPD subjects. Our emphysema protein score included 262 SOMAmers and predicted emphysema in AATD and COPD subjects. SOMAmer AAT level <7.99 relative fluorescence unit (RFU) had 100% sensitivity and specificity for identifying Pi*ZZ, but it was lower for other AATD genotypes. INTERPRETATION: Using SomaScan, we identified unique and shared plasma biomarkers between AATD and COPD subjects and generated a protein score that strongly associates with emphysema in COPD and AATD. Furthermore, we discovered unique biomarkers associated with DLCO and emphysema in PiZZ AATD. FUNDING: This work was supported by a grant from the Alpha-1 Foundation to RPB. COPDGene was supported by Award U01 HL089897 and U01 HL089856 from the National Heart, Lung, and Blood Institute. Proteomics for COPDGene was supported by NIH 1R01HL137995. GRADS was supported by Award U01HL112707, U01 HL112695 from the National Heart, Lung, and Blood Institute, and UL1TRR002535 to CCTSI; QUANTUM-1 was supported by the National Heart Lung and Blood Institute, the Office of Rare Diseases through the Rare Lung Disease Clinical Research Network (1 U54 RR019498-01, Trapnell PI), and the Alpha-1 Foundation. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion.

Statistical challenges posed by uncontrolled master protocols: sensitivity analysis of the vemurafenib study.

Within the evidentiary hierarchy of experimental inquiry, randomized trials are the gold standard. Oncology patients enter clinical studies with diverse lifestyles, treatment pathways, host tissue environments, and competing comorbidities. Randomization attempts to balance prognostic characteristics among study arms, thereby enabling statistical inference of 'average benefit' and attribution to the studied therapies. In contrast, interpretations of uncontrolled trials require additional scrutiny to attempt to place the findings in the context of external evidence. Counter-factual reasoning and speculation across trials may be obscured by the disproportionate enrollment of prognostic subpopulations which may be unknown from publications of trial reports. Recent modifications to the regulatory environment (Food and Drug Administration Safety and Innovation Act) have elevated the importance of non-comparative trials. Moreover, the emergence of recent innovations in precision medicine have yielded trial designs that partition potentially heterogeneous subpopulations into 'statistically exchangeable' cohorts by histologies, or genetic alterations, further elevating the importance of single-cohort analyses. As patient cohorts become ever more refined into smaller targeted subsets, consumers of reports of uncontrolled trials should be further empowered with improvements in reporting practices that better describe the enrolled prognostic subpopulations and importantly their association with study end points. This article demonstrates the issue with a sensitivity analysis of the findings reported in a recent trial that was devised to evaluate the preliminary clinical efficacy of vemurafenib in BRAF V600 mutation-positive nonmelanoma cancers.

Detection of unstable periodic orbits in mineralising geological systems.

Worldwide, mineral exploration is suffering from rising capital costs, due to the depletion of readily recoverable reserves and the need to discover and assess more inaccessible or geologically complex deposits. For gold exploration, this problem is particularly acute. We propose an innovative approach to mineral exploration and orebody characterisation, based on the analysis of geological core data as a spatial dynamical system, using the mathematical tools of dynamical system analysis. This approach is highly relevant for orogenic gold deposits, which-in contrast to systems formed at chemical equilibrium-exhibit many features of nonlinear dynamical systems, including episodic fluctuations on various length and time scales. Feedback relationships between thermo-chemical and deformation processes produce recurrent fluid temperatures and pressures and the deposition of vein-filling minerals such as pyrite and gold. We therefore relax the typical assumption of chemical equilibrium and analyse the underlying processes as aseismic, non-adiabatic, and inherent to a hydrothermal, nonlinear dynamical open-flow chemical reactor. These processes are approximated using the Gray-Scott model of reaction-diffusion as a complex toy system, which captures some of the features of the underlying mineralisation processes, including the spatiotemporal Turing patterns of unsteady chemical reactions. By use of this analysis, we demonstrate the capability of recurrence plots, recurrence power spectra, and recurrence time probabilities to detect underlying unstable periodic orbits as one sign of deterministic dynamics and their robustness for the analysis of data contaminated by noise. Recurrence plot based quantification is then applied to three mineral concentrations in the core data from the Sunrise Dam gold deposit in the Yilgarn region of Western Australia. Using a moving window, we reveal the episodic recurring low-dimensional dynamic structures and the period doubling route to instability with depth, embedded in and originating from higher-dimensional processes of the complex mineralisation system.

INTEGRATIVE BAYESIAN ANALYSIS OF NEUROIMAGING-GENETIC DATA THROUGH HIERARCHICAL DIMENSION REDUCTION.

Advances in neuromedicine have emerged from endeavors to elucidate the distinct genetic factors that influence the changes in brain structure that underlie various neurological conditions. We present a framework for examining the extent to which genetic factors impact imaging phenotypes described by voxel-wise measurements organized into collections of functionally relevant regions of interest (ROIs) that span the entire brain. Statistically, the integration of neuroimaging and genetic data is challenging. Because genetic variants are expected to impact different regions of the brain, an appropriate method of inference must simultaneously account for spatial dependence and model uncertainty. Our proposed framework combines feature extraction using generalized principal component analysis to account for inherent short- and long-range structural dependencies with Bayesian model averaging to effectuate variable selection in the presence of multiple genetic variants. The methods are demonstrated on a cocaine dependence study to identify ROIs associated with genetic factors that impact diffusion parameters.

Effects of domain shapes on the morphological evolution of nonaqueous-phase-liquid dissolution fronts in fluid-saturated porous media.

The main purpose of this paper is to investigate the effects of different domain shapes in general and trapezoidal domain shape in particular on the morphological evolution of nonaqueous phase liquid (NAPL) dissolution fronts in two-dimensional fluid-saturated porous media. After the governing equations of NAPL dissolution problems are briefly described, the numerical procedure consisting of a combination of the finite element and finite difference methods is used to solve these equations. The related numerical simulation results have demonstrated that: (1) domain shapes have a significant effect on both the propagating speed and the morphological evolution pattern of a NAPL dissolution front in the fluid-saturated porous medium; (2) an increase in the divergent angle of a trapezoidal domain can lead to a decrease in the propagating speed of the NAPL dissolution front; (3) the morphological evolution pattern of the NAPL dissolution front in a rectangular domain is remarkably different from that in a trapezoidal domain of a large divergent angle; (4) for a rectangular domain, the simplified dispersion model, which is commonly used in the theoretical analysis and numerical simulation, is valid for solving NAPL dissolution instability problems in fluid-saturated porous media; and (5) compared with diverging flow (when the trapezoidal domain is inclined outward), converging flow (when the trapezoidal domain is inclined inward) can enhance the growth of NAPL fingers, indicating that pump-and-treat systems by extracting contaminated groundwater might enhance NAPL dissolution fingering and lead to less uniform dissolution fronts.

Scalar dispersion in a periodically reoriented potential flow: acceleration via Lagrangian chaos.

Although potential flows are irrotational, Lagrangian chaos can occur when these are unsteady, with rapid global mixing observed upon flow parameter optimization. What is unknown is whether Lagrangian chaos in potential flows results in accelerated scalar dispersion, to what magnitude, how robustly, and via what mechanisms. We consider scalar dispersion in a model unsteady potential flow, the Lagrangian topology of which is well understood. The asymptotic scalar dispersion rate q and corresponding scalar distribution (strange eigenmode) are calculated over the flow parameter space Q for Peclét numbers Pe=10{1}-10{4}. The richness of solutions over Q increases with Pe, with pattern mode locking, symmetry breaking transitions to chaos and fractally distributed maxima observed. Such behavior suggests detailed global resolution of Q is necessary for robust optimization, however localization of local optima to bifurcations between periodic and subharmonic eigenmodes suggests novel efficient means of optimization. Acceleration rates of 150 fold at Pe=10{4} are observed; significantly greater than corresponding values for chaotic Stokes flows, suggesting significant scope for dispersion acceleration in potential flows in general.

On oscillating flows in randomly heterogeneous porous media.

The emergence of structure in reactive geofluid systems is of current interest. In geofluid systems, the fluids are supported by a porous medium whose physical and chemical properties may vary in space and time, sometimes sharply, and which may also evolve in reaction with the local fluids. Geofluids may also experience pressure and temperature conditions within the porous medium that drive their momentum relations beyond the normal Darcy regime. Furthermore, natural geofluid systems may experience forcings that are periodic in nature, or at least episodic. The combination of transient forcing, near-critical fluid dynamics and heterogeneous porous media yields a rich array of emergent geofluid phenomena that are only now beginning to be understood. One of the barriers to forward analysis in these geofluid systems is the problem of data scarcity. It is most often the case that fluid properties are reasonably well known, but that data on porous medium properties are measured with much less precision and spatial density. It is common to seek to perform an estimation of the porous medium properties by an inverse approach, that is, by expressing porous medium properties in terms of observed fluid characteristics. In this paper, we move toward such an inversion for the case of a generalized geofluid momentum equation in the context of time-periodic boundary conditions. We show that the generalized momentum equation results in frequency-domain responses that are governed by a second-order equation which is amenable to numerical solution. A stochastic perturbation approach demonstrates that frequency-domain responses of the fluids migrating in heterogeneous domains have spatial spectral densities that can be expressed in terms of the spectral densities of porous media properties.

Lagrangian topology of a periodically reoriented potential flow: symmetry, optimization, and mixing.

Scalar transport in closed potential flows is investigated for the specific case of a periodically reoriented dipole flow. Despite the irrotational nature of the flow, the periodic reorientations effectively create heteroclinic and/or homoclinic points arising from the joining of stable and unstable manifolds. For scalar advection, Lagrangian chaos can be achieved with breakdown of the regular Hamiltonian structure, which is governed by symmetry conditions imposed by the dipole flow. Instability envelopes associated with period-doubling bifurcations of fixed points govern which regions of the flow control parameter space admit global chaos. These regions are further refined via calculation of Lyapunov exponents. These results suggest significant scalar transport enhancement is possible within potential flows, given appropriate programming of stirring protocols.

Cardiovascular reactivity and initiate/avoid patterns of marital communication: a test of Gottman's psychophysiologic model of marital interaction.

Gottman's (1990, 1991; Gottman and Levenson, 1988) psychophysiologic model of marital interaction was tested in 60 married couples. Participants were classified as avoiders or initiators of relationship problem discussions by trained coders observing videotaped semistructured interviews. Blood pressure (BP) and heart rate reactivity was assessed during the cold pressor test, during a mental math test, while watching a marital argument on video, and during a conjoint interview. As hypothesized, avoiders had significantly greater systolic BP reactivity during the interview. Additionally, husbands who interacted with avoider wives had significantly greater diastolic and systolic BP reactivity than did husbands of initiator wives. Initiator husbands, in particular, who were married to avoider wives had greater systolic BP reactivity. These results both support Gottman's psychophysiologic model and suggest modifications of it.

Estimation of error and bias in Bayesian Monte Carlo decision analysis using the bootstrap.

Bayesian Monte Carlo (BMC) decision analysis adopts a sampling procedure to estimate likelihoods and distributions of outcomes, and then uses that information to calculate the expected performance of alternative strategies, the value of information, and the value of including uncertainty. These decision analysis outputs are therefore subject to sample error. The standard error of each estimate and its bias, if any, can be estimated by the bootstrap procedure. The bootstrap operates by resampling (with replacement) from the original BMC sample, and redoing the decision analysis. Repeating this procedure yields a distribution of decision analysis outputs. The bootstrap approach to estimating the effect of sample error upon BMC analysis is illustrated with a simple value-of-information calculation along with an analysis of a proposed control structure for Lake Erie. The examples show that the outputs of BMC decision analysis can have high levels of sample error and bias.

Using decision analysis to choose phosphorus targets for Lake Erie.

Lake Erie water quality has improved dramatically since the degraded conditions of the 1960s. Additional gains could be made, but at the expense of further investment and reductions in fishery productivity. In facing such cross-jurisdictional issues, natural resource managers in Canada and the United States must grapple with conflicting objectives and important uncertainties, while considering the priorities of the public that live in the basin. The techniques and tools of decision analysis have been used successfully to deal with such decision problems in a range of environmental settings, but infrequently in the Great Lakes. The objective of this paper is to illustrate how such techniques might be brought to bear on an important, real decision currently facing Lake Erie resource managers and stakeholders: the choice of new phosphorus loading targets for the lake. The heart of our approach is a systematic elicitation of stakeholder preferences and an investigation of the degree to which different phosphorus-loading policies might satisfy ecosystem objectives. Results show that there are potential benefits to changing the historical policy of reducing phosphorus loads in Lake Erie.

A randomized trial of emotion-focused therapy for couples in a training clinic.

Forty married couples participated in a randomized trial comparing 8 weekly sessions of emotion-focused therapy (EFT) for couples to a group of couples who were placed on an 8-week waiting list. A composite marital satisfaction score was created from scores on the Dyadic Adjustment Scale, Positive Feelings Questionnaire, and Personal Assessment of Intimacy in Relationships scale. Controlling for pretest scores, participants in the treatment group had significantly higher levels of marital satisfaction after 8 weeks than wait-list participants. Supplementary analyses identified variables associated with gains in therapy and with dropping out of the study.

Need for radiologists to interpret orthopedic total joint radiographs.

We applaud the aim of Nayak and colleagues: to use our scarce economic resources as judiciously as possible. We have suggested several alternatives that would save more of our scarce health care dollars. We would be delighted to take part in a properly designed prospective randomized trial to address the issues presented in this paper. We believe the literature would be strengthened by the publication of a collegial paper, coauthored by orthopedic and radiology departments, addressing the issue of saving health care dollars by omitting unnecessary or redundant procedures.

Shigella isolates in stool.

A total of 447 Shigella strains were isolated from stool samples during 1989-1991. Of these 270 (60%) were from children. Among the different species and serotypes Sh. flexneri 60 (13.4%) and Sh. sonnei Phage 139 (65%) were the most frequently isolated strains. 154 (34.4%) strains were resistant to three and 179 (40%) to more than three antibiotics. Some strains of Shigella were found to be resistant to furazolidine and neomycin.

A guide to strategic planning.

Strategic planning is a new concept in general practice. Underneath all the jargon, however, it is simply a label for the planning and evaluation processes that most organisations have used in the past. The aim of this paper is to demystify strategic planning as it applies to newly formed Divisions of General Practice.