Validation and Calibration of a Computer Simulation Model of Pediatric HIV Infection

Background

Computer simulation models can project long-term patient outcomes and inform health policy. We internally validated and then calibrated a model of HIV disease in children before initiation of antiretroviral therapy to provide a framework against which to compare the impact of pediatric HIV treatment strategies.

Methods

We developed a patient-level (Monte Carlo) model of HIV progression among untreated children <5 years of age, using the Cost-Effectiveness of Preventing AIDS Complications model framework: the CEPAC-Pediatric model. We populated the model with data on opportunistic infection and mortality risks from the International Epidemiologic Database to Evaluate AIDS (IeDEA), with mean CD4% at birth (42%) and mean CD4% decline (1.4%/month) from the Women and Infants’ Transmission Study (WITS). We internally validated the model by varying WITS-derived CD4% data, comparing the corresponding model-generated survival curves to empirical survival curves from IeDEA, and identifying best-fitting parameter sets as those with a root-mean square error (RMSE) <0.01. We then calibrated the model to other African settings by systematically varying immunologic and HIV mortality-related input parameters. Model-generated survival curves for children aged 0-60 months were compared, again using RMSE, to UNAIDS data from >1,300 untreated, HIV-infected African children.

Results

In internal validation analyses, model-generated survival curves fit IeDEA data well; modeled and observed survival at 16 months of age were 91.2% and 91.1%, respectively. RMSE varied widely with variations in CD4% parameters; the best fitting parameter set (RMSE = 0.00423) resulted when CD4% was 45% at birth and declined by 6%/month (ages 0-3 months) and 0.3%/month (ages >3 months). In calibration analyses, increases in IeDEA-derived mortality risks were necessary to fit UNAIDS survival data.

Conclusions

The CEPAC-Pediatric model performed well in internal validation analyses. Increases in modeled mortality risks required to match UNAIDS data highlight the importance of pre-enrollment mortality in many pediatric cohort studies.     

Olfactory Thresholds of the U.S. Population of Home-Dwelling Older Adults: Development and Validation of a Short,Reliable Measure

Current methods of olfactory sensitivity testing are logistically challenging and therefore infeasible for use in in-home surveys and other field settings. We developed a fast, easy and reliable method of assessing olfactory thresholds, and used it in the first study of olfactory sensitivity in a nationally representative sample of U.S. home-dwelling older adults. We validated our method via computer simulation together with a model estimated from 590 normosmics. Simulated subjects were assigned n-butanol thresholds drawn from the estimated normosmic distribution and based on these and the model, we simulated administration of both the staircase and constant stimuli methods. Our results replicate both the correlation between the two methods and their reliability as previously reported by studies using human subjects. Further simulations evaluated the reliability of different constant stimuli protocols, varying both the range of dilutions and number of stimuli (6–16). Six appropriately chosen dilutions were sufficient for good reliability (0.67) in normosmic subjects. Finally, we applied our method to design a 5-minute, in-home assessment of older adults (National Social Life, Health and Aging Project, or NSHAP), which had comparable reliability (0.56), despite many subjects having estimated thresholds above the strongest dilution. Thus, testing with a fast, 6-item constant stimuli protocol is informative, and permits olfactory testing in previously inaccessible research settings.     

美国州立公园体系的发展、特征与评估

美国州立公园与国家公园相比,更强调满足州内居民就近户外休闲游憩需求的功能,这使得其在美国整体公共户外休闲空间体系中占据特殊的位置。在中国第一次全面地研究了美国州立公园体系的发展、特征及与国家公园体系的关系,特别是以部分州为例研究了美国州立公园的分类、质量评估、可达性与空间分布评估等关键问题。研究认为,州立公园的意义在于既缓解了美国国家公园面临的巨大旅游游憩压力,也满足了大众户外休闲游憩的需求。这值得中国在目前构建国家公园与自然保护地体系的同时予以借鉴。最后基于中国的实际需求与挑战,探讨了在省域/区域层次加强构建地方公园、保护地和游憩地体系建设的必要性与途径。     

Clinical,Molecular and Genetic Validation of a Murine Orthotopic Xenograft Model of Pancreatic Adenocarcinoma Using Fresh Human Specimens

Background

Relevant preclinical models that recapitulate the key features of human pancreatic ductal adenocarcinoma (PDAC) are needed in order to provide biologically tractable models to probe disease progression and therapeutic responses and ultimately improve patient outcomes for this disease. Here, we describe the establishment and clinical, pathological, molecular and genetic validation of a murine, orthotopic xenograft model of PDAC.

Methods

Human PDACs were resected and orthotopically implanted and propagated in immunocompromised mice. Patient survival was correlated with xenograft growth and metastatic rate in mice. Human and mouse tumor pathology were compared. Tumors were analyzed for genetic mutations, gene expression, receptor tyrosine kinase activation, and cytokine expression.

Results

Fifteen human PDACs were propagated orthotopically in mice. Xenograft-bearing mice developed peritoneal and liver metastases. Time to tumor growth and metastatic efficiency in mice each correlated with patient survival. Tumor architecture, nuclear grade and stromal content were similar in patient and xenografted tumors. Propagated tumors closely exhibited the genetic and molecular features known to characterize pancreatic cancer (e.g. high rate of KRAS, P53, SMAD4 mutation and EGFR activation). The correlation coefficient of gene expression between patient tumors and xenografts propagated through multiple generations was 93 to 99%. Analysis of gene expression demonstrated distinct differences between xenografts from fresh patient tumors versus commercially available PDAC cell lines.

Conclusions

The orthotopic xenograft model derived from fresh human PDACs closely recapitulates the clinical, pathologic, genetic and molecular aspects of human disease. This model has resulted in the identification of rational therapeutic strategies to be tested in clinical trials and will permit additional therapeutic approaches and identification of biomarkers of response to therapy.     

Beyond Black and White: New Faces and Voices in U.S. Schools

Beyond Black and White: New Faces and Voices in U.S. Schools. Maxine Seller and Lois Weis, eds. Albany: State University of New York Press, 1997. 328 pp.     

Body Mass Index and All-Cause Mortality in a Large Prospective Cohort of White and Black U.S. Adults

Remaining controversies on the association between body mass index (BMI) and mortality include the effects of smoking and prevalent disease on the association, whether overweight is associated with higher mortality rates, differences in associations by race and the optimal age at which BMI predicts mortality. To assess the relative risk (RR) of mortality by BMI in Whites and Blacks among subgroups defined by smoking, prevalent disease, and age, 891,572 White and 38,119 Black men and women provided height, weight and other information when enrolled in the Cancer Prevention Study II in 1982. Over 28 years of follow-up, there were 434,400 deaths in Whites and 18,702 deaths in Blacks. Cox proportional-hazards regression was used to estimate multivariable-adjusted relative risks (RR) and 95% confidence intervals (CI). Smoking and prevalent disease status significantly modified the BMI-mortality relationship in Whites and Blacks; higher BMI was most strongly associated with higher risk of mortality among never smokers without prevalent disease. All levels of overweight and obesity were associated with a statistically significantly higher risk of mortality compared to the reference category (BMI 22.5–24.9 kg/m²), except among Black women where risk was elevated but not statistically significant in the lower end of overweight. Although absolute mortality rates were higher in Blacks than Whites within each BMI category, relative risks (RRs) were similar between race groups for both men and women (p-heterogeneity by race  = 0.20 for men and 0.23 for women). BMI was most strongly associated with mortality when reported before age 70 years. Results from this study demonstrate for the first time that the BMI-mortality relationship differs for men and women who smoke or have prevalent disease compared to healthy never-smokers. These findings further support recommendations for maintaining a BMI between 20–25 kg/m² for optimal health and longevity.     

Construction, MD Simulation, and Hydrodynamic Validation of an All-Atom Model of a Monoclonal IgG Antibody

At 150 kDa, antibodies of the IgG class are too large for their structure to be determined with current NMR methodologies. Because of hinge-region flexibility, it is difficult to obtain atomic-level structural information from the crystal, and questions regarding antibody structure and dynamics in solution remain unaddressed. Here we describe the construction of a model of a human IgG1 monoclonal antibody (trastuzumab) from the crystal structures of fragments. We use a combination of molecular-dynamics (MD) simulation, continuum hydrodynamics modeling, and experimental diffusion measurements to explore antibody behavior in aqueous solution. Hydrodynamic modeling provides a link between the atomic-level details of MD simulation and the size- and shape-dependent data provided by hydrodynamic measurements. Eight independent 40 ns MD trajectories were obtained with the AMBER program suite. The ensemble average of the computed transport properties over all of the MD trajectories agrees remarkably well with the value of the translational diffusion coefficient obtained with dynamic light scattering at 20°C and 27°C, and the intrinsic viscosity measured at 20°C. Therefore, our MD results likely represent a realistic sampling of the conformational space that an antibody explores in aqueous solution.     

Population-Level Correlates of Preterm Delivery among Black and White Women in the U.S

Objective

This study examined the ability of social, demographic, environmental and health-related factors to explain geographic variability in preterm delivery among black and white women in the US and whether these factors explain black-white disparities in preterm delivery.

Methods

We examined county-level prevalence of preterm delivery (20–31 or 32–36 weeks gestation) among singletons born 1998–2002. We conducted multivariable linear regression analysis to estimate the association of selected variables with preterm delivery separately for each preterm/race-ethnicity group.

Results

The prevalence of preterm delivery varied two- to three-fold across U.S. counties, and the distributions were strikingly distinct for blacks and whites. Among births to blacks, regression models explained 46% of the variability in county-level risk of delivery at 20–31 weeks and 55% for delivery at 32–36 weeks (based on R-squared values). Respective percentages for whites were 67% and 71%. Models included socio-environmental/demographic and health-related variables and explained similar amounts of variability overall.

Conclusions

Much of the geographic variability in preterm delivery in the US can be explained by socioeconomic, demographic and health-related characteristics of the population, but less so for blacks than whites.     

Postcranial skeleton of a Neandertal child from Kiik-Koba, U.S.S.R.

A study of the skeletal remains of a Neandertal child from Kiik-Koba has brought to light some features that are typical of adult Neandertal individuals from Europe. Therefore, the ascertained differences in the proportions of the individual parts of upper and lower limbs, as well as a number of marked morphological features, such as the robusticity of ribs, typical Neandertal features of the scapula, curving of forearm bones, back-to-front curving of the femoral diaphysis, retroversion of the upper epiphysis of the tibia, and robusticity of long bones in the Neandertal individual at the age of infans I, may be regarded as phylogenetically ingrained ones. These may in their turn be considered diagnostic features, of importance in determining the phylogenetic classification of postcranial skeletal remains in the development of man.     

水稻生长模拟模型的组建与验证

在模型L1D和TIL的基础上,利用田间试验和文献资料,组建了水稻生长过程的动态模拟模型．验证结果显示,模型运行后生育期的模拟值与实测值吻合良好,干物重、叶面积系数和分蘖数的模拟值与实测值也基本一致,表明该模型能较好地模拟水稻生长过程的动态变化．     

U.S. Federal Initiatives to Support Biomass Research and Development

This article provides a brief overview of federal initiatives in the United States to support biomass research, demonstration, and development. The interest in the biomass industry and U.S. federal efforts to spur development of, increased production of, and use of biopower, biofuels, and biobased products, collectively known as the "biomass industry", are discussed. A growing level of leadership from the executive branch of the federal government and support by the U.S. Congress are documented. Five important policy drivers that support this heightened emphasis on biomass for power, fuels, and products are identified and discussed. The current status of U.S. dependence on these renewable energy sources is briefly outlined. Federal biomass funding activity for the current fiscal year by the U.S. Department of Agriculture and the U.S. Department of Energy, two major federal participants in research, demonstration, and development for this industry, is briefly outlined. This funding commitment is placed into an overall context of total federal support for all research and development. Finally, the article suggests future market penetration targets for this industry, emphasizes the importance of infrastructure development necessary to support the industry's growth, and notes the payoff from such development for farmers, foresters, rural communities, and the environment.     

Comprehensive,Population-Based Sensitivity Analysis of a Two-Mass Vocal Fold Model

Previous vocal fold modeling studies have generally focused on generating detailed data regarding a narrow subset of possible model configurations. These studies can be interpreted to be the investigation of a single subject under one or more vocal conditions. In this study, a broad population-based sensitivity analysis is employed to examine the behavior of a virtual population of subjects and to identify trends between virtual individuals as opposed to investigating a single subject or model instance. Four different sensitivity analysis techniques were used in accomplishing this task. Influential relationships between model input parameters and model outputs were identified, and an exploration of the model’s parameter space was conducted. Results indicate that the behavior of the selected two-mass model is largely dominated by complex interactions, and that few input-output pairs have a consistent effect on the model. Results from the analysis can be used to increase the efficiency of optimization routines of reduced-order models used to investigate voice abnormalities. Results also demonstrate the types of challenges and difficulties to be expected when applying sensitivity analyses to more complex vocal fold models. Such challenges are discussed and recommendations are made for future studies.     

Risk Prediction for Breast,Endometrial, and Ovarian Cancer in White Women Aged 50 y or Older: Derivation and Validation from Population-Based Cohort Studies

Background

Breast, endometrial, and ovarian cancers share some hormonal and epidemiologic risk factors. While several models predict absolute risk of breast cancer, there are few models for ovarian cancer in the general population, and none for endometrial cancer.

Methods and Findings

Using data on white, non-Hispanic women aged 50+ y from two large population-based cohorts (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [PLCO] and the National Institutes of Health–AARP Diet and Health Study [NIH-AARP]), we estimated relative and attributable risks and combined them with age-specific US-population incidence and competing mortality rates. All models included parity. The breast cancer model additionally included estrogen and progestin menopausal hormone therapy (MHT) use, other MHT use, age at first live birth, menopausal status, age at menopause, family history of breast or ovarian cancer, benign breast disease/biopsies, alcohol consumption, and body mass index (BMI); the endometrial model included menopausal status, age at menopause, BMI, smoking, oral contraceptive use, MHT use, and an interaction term between BMI and MHT use; the ovarian model included oral contraceptive use, MHT use, and family history or breast or ovarian cancer. In independent validation data (Nurses'' Health Study cohort) the breast and ovarian cancer models were well calibrated; expected to observed cancer ratios were 1.00 (95% confidence interval [CI]: 0.96–1.04) for breast cancer and 1.08 (95% CI: 0.97–1.19) for ovarian cancer. The number of endometrial cancers was significantly overestimated, expected/observed = 1.20 (95% CI: 1.11–1.29). The areas under the receiver operating characteristic curves (AUCs; discriminatory power) were 0.58 (95% CI: 0.57–0.59), 0.59 (95% CI: 0.56–0.63), and 0.68 (95% CI: 0.66–0.70) for the breast, ovarian, and endometrial models, respectively.

Conclusions

These models predict absolute risks for breast, endometrial, and ovarian cancers from easily obtainable risk factors and may assist in clinical decision-making. Limitations are the modest discriminatory ability of the breast and ovarian models and that these models may not generalize to women of other races. Please see later in the article for the Editors'' Summary     

Dry Matter Partitioning in Tomato: Validation of a Dynamic Simulation Model

A model for dynamic simulation of dry matter distribution betweenreproductive and vegetative plant parts and the distributionamong individual fruit trusses in glasshouse tomato, is validated.The model is part of the crop growth model TOMSIM and is basedon the hypothesis that dry matter distribution is regulatedby the sink strengths of the plant organs, quantified by theirpotential growth rates, i.e. the growth rates at non-limitingassimilate supply. Within the plant, individual fruit trussesare distinguished and sink strength of a truss is describedas a function of its development stage. Truss development rateis a function of temperature only. The same potential growthcurve, proportional to the number of fruits per truss, is adoptedfor all trusses. In a simple version of the model, vegetativeplant parts are lumped together as one sink with a constantsink strength. In a more detailed version, vegetative sink strengthis calculated as the sum of sink strengths of vegetative units(three leaves and stem internodes between two trusses). The model was validated for six glasshouse experiments, coveringeffects of planting date, plant density, number of fruits pertruss (pruning at anthesis), truss removal (every second trussremoved at anthesis), single- and double-shoot plants and atemperature experiment conducted in climate rooms at 17, 20or 23 °C. Daily increase in above-ground dry weight, averagedaily temperatures and number of set fruits per truss were inputsto the model. Both the simple and the more detailed model showedgood agreement between measured and simulated fraction of drymatter partitioned into the fruits over time. For the simpleversion of the model, the slope of the lines relating simulatedto measured fraction partitioned into the fruits (16 data sets),varied between 0.92 and 1.11, on average it was 1.04, implying4% over-estimation for this fraction. For the detailed modelthese numbers were slightly better: 0.89, 1.08 and 1.01, respectively.The temperature experiment revealed no important direct influenceof temperature on the ratio between generative and vegetativesink strength. Simulated truss growth curves showed reasonableagreement with the measurements, although both models over-estimated(17% on average) final dry weight of the lower trusses (truss1 –3) on a plant. Modelling dry matter partitioning basedon sink strengths of organs is promising, as it is a general,dynamic and flexible approach, showing good agreement betweenmeasurements and simulation for a range of conditions. Applicabilityof the model is, however, still limited as long as the numberof fruits per truss (flower and /or fruit abortion) is not simulated,as this is a major feedback mechanism in plant growth. Dry matter distribution; sink strength; glasshouse; model; partitioning; simulation; temperature; tomato; TOMSIM; validation     

Development of a new version of the Liverpool Malaria Model. II. Calibration and validation for West Africa

Mathematical models have been used to provide an explicit framework for understanding malaria transmission dynamics in human population for over 100 years. With the disease still thriving and threatening to be a major source of death and disability due to changed environmental and socio-economic conditions, it is necessary to make a critical assessment of the existing models, and study their evolution and efficacy in describing the host-parasite biology. In this article, starting from the basic Ross model, the key mathematical models and their underlying features, based on their specific contributions in the understanding of spread and transmission of malaria have been discussed. The first aim of this article is to develop, starting from the basic models, a hierarchical structure of a range of deterministic models of different levels of complexity. The second objective is to elaborate, using some of the representative mathematical models, the evolution of modelling strategies to describe malaria incidence by including the critical features of host-vector-parasite interactions. Emphasis is more on the evolution of the deterministic differential equation based epidemiological compartment models with a brief discussion on data based statistical models. In this comprehensive survey, the approach has been to summarize the modelling activity in this area so that it helps reach a wider range of researchers working on epidemiology, transmission, and other aspects of malaria. This may facilitate the mathematicians to further develop suitable models in this direction relevant to the present scenario, and help the biologists and public health personnel to adopt better understanding of the modelling strategies to control the disease     

Alethopteris ambigua Lesquereux, a Pennsylvanian pteridosperm from Missouri, U.S.A.

Transfers and macerations of Alethopteris ambigua Lesquereux reveal it as axeromorphio plant. The papillose lower epidermis of each pinnule is sheltered by incurved pinnule margins, a bladelike extension of the midvein and by marginal hairs. Preservation is such that cellular outlines are discernible on all but the cuticles of the lower epidermis.     

Extreme hydrologic banding in a large-river Floodplain, California, U.S.A.

Where tributaries meet, certain conditions of flow and topography often result in incomplete mixing and the formation of spatially and temporally persistent plumes or bands. Yolo Bypass, the primary floodplain of the lower Sacramento River (California, USA), provides an extreme example of this effect. Inspection of recent and historical aerial photographs revealed that the four major tributaries of Yolo Bypass typically do not substantially mix laterally within the floodplain. The phenomenon is notable in the number of tributaries involved (4), the distance over which the bands remain distinct (>61 km), and the persistence of the bands despite channel constrictions and long cross-wind fetch. This effect demonstrates the importance of lateral variability during floodplain flow events, including transport and distribution of chemical constituents, and habitat for fish and other organisms that use floodplains as migration corridors and rearing areas. Handling editor: S. M. Thomaz