SOP: Parallel surrogate global optimization with Pareto center selection for computationally expensive single objective problems

This paper presents a parallel surrogate-based global optimization method for computationally expensive objective functions that is more effective for larger numbers of processors. To reach this goal, we integrated concepts from multi-objective optimization and tabu search into, single objective, surrogate optimization. Our proposed derivative-free algorithm, called SOP, uses non-dominated sorting of points for which the expensive function has been previously evaluated. The two objectives are the expensive function value of the point and the minimum distance of the point to previously evaluated points. Based on the results of non-dominated sorting, P points from the sorted fronts are selected as centers from which many candidate points are generated by random perturbations. Based on surrogate approximation, the best candidate point is subsequently selected for expensive evaluation for each of the P centers, with simultaneous computation on P processors. Centers that previously did not generate good solutions are tabu with a given tenure. We show almost sure convergence of this algorithm under some conditions. The performance of SOP is compared with two RBF based methods. The test results show that SOP is an efficient method that can reduce time required to find a good near optimal solution. In a number of cases the efficiency of SOP is so good that SOP with 8 processors found an accurate answer in less wall-clock time than the other algorithms did with 32 processors.

Estimating parameters in Markov models for longitudinal studies with missing data or surrogate outcomes

The discrete-time Markov chain is commonly used in describing changes of health states for chronic diseases in a longitudinal study. Statistical inferences on comparing treatment effects or on finding determinants of disease progression usually require estimation of transition probabilities. In many situations when the outcome data have some missing observations or the variable of interest (called a latent variable) can not be measured directly, the estimation of transition probabilities becomes more complicated. In the latter case, a surrogate variable that is easier to access and can gauge the characteristics of the latent one is usually used for data analysis. ^ This dissertation research proposes methods to analyze longitudinal data (1) that have categorical outcome with missing observations or (2) that use complete or incomplete surrogate observations to analyze the categorical latent outcome. For (1), different missing mechanisms were considered for empirical studies using methods that include EM algorithm, Monte Carlo EM and a procedure that is not a data augmentation method. For (2), the hidden Markov model with the forward-backward procedure was applied for parameter estimation. This method was also extended to cover the computation of standard errors. The proposed methods were demonstrated by the Schizophrenia example. The relevance of public health, the strength and limitations, and possible future research were also discussed. ^

Determining appropriate measurement methods for etiological research of computing-related musculoskeletal symptoms and disorders

Two studies among college students were conducted to evaluate appropriate measurement methods for etiological research on computing-related upper extremity musculoskeletal disorders (UEMSDs). ^ A cross-sectional study among 100 graduate students evaluated the utility of symptoms surveys (a VAS scale and 5-point Likert scale) compared with two UEMSD clinical classification systems (Gerr and Moore protocols). The two symptom measures were highly concordant (Lin's rho = 0.54; Spearman's r = 0.72); the two clinical protocols were moderately concordant (Cohen's kappa = 0.50). Sensitivity and specificity, endorsed by Youden's J statistic, did not reveal much agreement between the symptoms surveys and clinical examinations. It cannot be concluded self-report symptoms surveys can be used as surrogate for clinical examinations. ^ A pilot repeated measures study conducted among 30 undergraduate students evaluated computing exposure measurement methods. Key findings are: temporal variations in symptoms, the odds of experiencing symptoms increased with every hour of computer use (adjOR = 1.1, p < .10) and every stretch break taken (adjOR = 1.3, p < .10). When measuring posture using the Computer Use Checklist, a positive association with symptoms was observed (adjOR = 1.3, p < 0.10), while measuring posture using a modified Rapid Upper Limb Assessment produced unexpected and inconsistent associations. The findings were inconclusive in identifying an appropriate posture assessment or superior conceptualization of computer use exposure. ^ A cross-sectional study of 166 graduate students evaluated the comparability of graduate students to College Computing & Health surveys administered to undergraduate students. Fifty-five percent reported computing-related pain and functional limitations. Years of computer use in graduate school and number of years in school where weekly computer use was ≥ 10 hours were associated with pain within an hour of computing in logistic regression analyses. The findings are consistent with current literature on both undergraduate and graduate students. ^

Rigorous design of distillation columns using surrogate models based on Kriging interpolation

The economic design of a distillation column or distillation sequences is a challenging problem that has been addressed by superstructure approaches. However, these methods have not been widely used because they lead to mixed-integer nonlinear programs that are hard to solve, and require complex initialization procedures. In this article, we propose to address this challenging problem by substituting the distillation columns by Kriging-based surrogate models generated via state of the art distillation models. We study different columns with increasing difficulty, and show that it is possible to get accurate Kriging-based surrogate models. The optimization strategy ensures that convergence to a local optimum is guaranteed for numerical noise-free models. For distillation columns (slightly noisy systems), Karush–Kuhn–Tucker optimality conditions cannot be tested directly on the actual model, but still we can guarantee a local minimum in a trust region of the surrogate model that contains the actual local minimum.

Optimization of Chemical Processes Using Surrogate Models Based on a Kriging Interpolation

Superstructure approaches are the solution to the difficult problem which involves the rigorous economic design of a distillation column. These methods require complex initialization procedures and they are hard to solve. For this reason, these methods have not been extensively used. In this work, we present a methodology for the rigorous optimization of chemical processes implemented on a commercial simulator using surrogate models based on a kriging interpolation. Several examples were studied, but in this paper, we perform the optimization of a superstructure for a non-sharp separation to show the efficiency and effectiveness of the method. Noteworthy that it is possible to get surrogate models accurate enough with up to seven degrees of freedom.

Somatic cell gene therapy for diabetes mellitus: engineering a surrogate B-cell

Improved methods of insulin delivery are required for the treatment of insulin-dependent diabetes mellitus (IDDM) to achieve a more physiological profile of glucose homeostasis. Somatic cell gene therapy offers the prospect that insulin could be delivered by an autologous cell implant, engineered to secrete insulin in response to glucose. This study explores the feasibility of manipulating somatic cells to behave as a surrogate insulin-secreting β-cells. Initial studies were conducted using mouse pituitary AtT20 cells as a model, since these cells possess an endogenous complement of enzymes capable of processing proinsulin to mature insulin. Glucose sensitive insulin secretion was conferred to these cells by transfection with plasmids containing the human preproinsulin gene (hppI-1) and the GLUT2 gene for the glucose transporter isoform 2. Insulin secretion was responsive to changes in the glucose concentration up to about 50μM. Further studies to up-rate this glucose sensitivity into the mM range will require manipulation of the hexokinase and glucokinase enzymes. Intraperitoneal implantation of the manipulated AtT20 cells into athymic nude mice with streptozotocin-induced diabetes resulted in decreased plasma glucose concentrations. The cells formed vascularised tumours in vivo which were shown to contain insulin-secreting cells. To achieve proinsulin processing in non-endocrine cells, co-transfection with a suitable enzyme, or mutagenesis of the proinsulin itself are necessary. The mutation of the human preproinsulin gene to the consensus sequence for cleavage by the subtilisin-like serine protease, furin, was carried out. Co-transfection of human fibroblasts with wild-type proinsulin and furin resulted in 58% conversion to mature insulin by these cells. Intraperitoneal implantation of the mature-insulin secreting human fibroblasts into the diabetic nude mouse animal model gave less encouraging results than the AtT20 cells, apparently due to poor vascularisation. Cell aggregations removed from the mice at autopsy were shown to contain insulin secreting cells only at the periphery. This thesis provides evidence that it is possible to construct, by cellular engineering, a glucose-sensitive insulin-secreting surrogate β-cell. Therefore, somatic cell gene therapy offers a feasible alternative for insulin delivery in IDDM patients.

How accurate are photographic surrogate markers used to detect macular edema in the English national screening programme?

DESIGN. Retrospective analysis PURPOSE. Macular oedema is not directly visible on two dimensional digital photographs such that surrogate markers need to be used. In the English National Screening Programme these are exudate within one optic disc diameter (DD) of the fovea, group of exudates within two DD of the fovea and haemorrhages or microaneurysms (HMA) within one DD of the fovea with best corrected visual acuity (VA) worse than 6/9. All patients who present with any of these surrogate markers at screening are referred to an ophthalmology clinic for slit lamp examination. The purpose of this audit was to determine how many patients with positive maculopathy diagnosis on photography were truly identified by optical coherence tomography (OCT) with macular oedema. METHODS. Data was collected from patients attending digital diabetic retinopathy screening. Patients who presented with surrogate markers for macular oedema also had an OCT scan. The fast macula scan on the Stratus OCT was used and an ophthalmologist reviewed the scans to determine whether macular oedema was present. RESULTS. Maculopathy by exudates: Of 155 patients 45 (29%) showed thickening on the OCT of these 12 required laser. Those who also had pre-proliferative retinopathy (n=20) were more likely to have macular oedema (75%) than those with background diabetic retinopathy. Maculopathy by HMA and VA worse than 6/9: Of 66 patients 11 (16.7%) showed thickening on the OCT. 5 (7.6%) of these had macular oedema, 5 (7.6%) epi-retinal membrane, and 1 (1.5%) age related macular degeneration. None of these patients required laser. CONCLUSIONS. The likelihood of the presence of macular oedema and requiring laser treatment is greater with macular exudation than HMA within one DD and reduced VA. Overall the surrogate markers used show low specificity for macular oedema, however combining OCT with photography does identify those with macular oedema who require a true referral for an ophthalmological slit lamp examination.

An Ethical and Legal Framework for Physicians as Surrogate Decision-Makers for Their Patients.

In Western industrialized countries, it is well established that legally competent individuals may choose a surrogate healthcare decision-maker to represent their interests should they lose the capacity to do so themselves. There are few limitations on who they may select to fulfill this function. However, many jurisdictions place restrictions on or prohibit the patient's attending physician or other provider involved with an individual's care to serve in this role. Several authors have previously suggested that respect for the autonomy of patients requires that there be few (if any) constraints on whomever they may appoint as a proxy. In this essay we revisit this topic by first providing a survey of current state laws governing this activity. We then analyze the clinical and ethical circumstances in which potential difficulties could arise. We take a more nuanced and circumspect view of prior suggestions that patients should have virtually unfettered liberty to choose their healthcare proxies. We suggest a strategy to balance the freedom of patients' right to choose their surrogates with fiduciary duty of the state as regulator of medical practice. We identify six domains of possible concern with such relationships and suggest straightforward methods of mitigating their potential negative effects that could be plausibly be incorporated into physician practice.

Extracellular cathepsin S and intracellular caspase 1 activation are surrogate biomarkers of particulate-induced lysosomal disruption in macrophages

BACKGROUND: Particulate matter has been shown to stimulate the innate immune system and induce acute inflammation. Therefore, while nanotechnology has the potential to provide therapeutic formulations with improved efficacy, there are concerns such pharmaceutical preparations could induce unwanted inflammatory side effects. Accordingly, we aim to examine the utility of using the proteolytic activity signatures of cysteine proteases, caspase 1 and cathepsin S (CTSS), as biomarkers to assess particulate-induced inflammation.

METHODS: Primary peritoneal macrophages and bone marrow-derived macrophages from C57BL/6 mice and ctss(-/-) mice were exposed to micro- and nanoparticulates and also the lysosomotropic agent, L-leucyl-L-leucine methyl ester (LLOME). ELISA and immunoblot analyses were used to measure the IL-1β response in cells, generated by lysosomal rupture. Affinity-binding probes (ABPs), which irreversibly bind to the active site thiol of cysteine proteases, were then used to detect active caspase 1 and CTSS following lysosomal rupture. Reporter substrates were also used to quantify the proteolytic activity of these enzymes, as measured by substrate turnover.

RESULTS: We demonstrate that exposure to silica, alum and polystyrene particulates induces IL-1β release from macrophages, through lysosomal destabilization. IL-1β secretion positively correlated with an increase in the proteolytic activity signatures of intracellular caspase 1 and extracellular CTSS, which were detected using ABPs and reporter substrates. Interestingly IL-1β release was significantly reduced in primary macrophages from ctss(-/-) mice.

CONCLUSIONS: This study supports the emerging significance of CTSS as a regulator of the innate immune response, highlighting its role in regulating IL-1β release. Crucially, the results demonstrate the utility of intracellular caspase 1 and extracellular CTSS proteolytic activities as surrogate biomarkers of lysosomal rupture and acute inflammation. In the future, activity-based detection of these enzymes may prove useful for the real-time assessment of particle-induced inflammation and toxicity assessment during the development of nanotherapeutics.