Design evaluation and optimization for models of hepatitis C viral dynamics

Mathematical modeling of hepatitis C viral (HCV) kinetics is widely used for understanding viral pathogenesis and predicting treatment outcome. The standard model is based on a system of five non-linear ordinary differential equations (ODE) that describe both viral kinetics and changes in drug concentration after treatment initiation. In such complex models parameter estimation is challenging and requires frequent sampling measurements on each individual. By borrowing information between study subjects, non-linear mixed effect models can deal with sparser sampling from each individual. However, the search for optimal designs in this context has been limited by the numerical difficulty of evaluating the Fisher information matrix (FIM). Using the software PFIM, we show that a linearization of the statistical model avoids most of the computational burden, while providing a good approximation to the FIM. We then compare the precision of the parameters that can be expected using five study designs from the literature. We illustrate the usefulness of rationalizing data sampling by showing that, for a given level of precision, optimal design could reduce the total number of measurements by up 50 per cent. Our approach can be used by a statistician or a clinician aiming at designing an HCV viral kinetics study.     

World Health Organization hemoglobin cut-off points for the detection of anemia are valid for an Indonesian population.

The study was designed to determine whether population-specific hemoglobin cut-off values for detection of iron deficiency are needed for Indonesia by comparing the hemoglobin distribution of healthy young Indonesians with that of an American population. This was a cross-sectional study in 203 males and 170 females recruited through a convenience sampling procedure. Hemoglobin, iron biochemistry tests and key infection indicators that can influence iron metabolism were analyzed. The hemoglobin distributions, based on individuals without evidence of clear iron deficiency and infectious process, were compared with the National Health and Nutrition Survey (NHANES) II population of the United States. Twenty percent of the Indonesian females had iron deficiency, but no male subjects were iron deficient. The mean hemoglobin of Indonesian males was similar to the American reference population at 152 g/L with comparable hemoglobin distribution. The mean hemoglobin of the Indonesian females was 2 g/L lower than that of the American reference population, which may be the result of incomplete exclusion of subjects with milder form of iron deficiency. When the WHO cutoff (Hb < 120 g/L) was applied to female subjects, the sensitivity of 34.2% and specificity of 89.4% were more comparable to the test performance for white American women, in contrast to those of the lower cut-off. On the basis of the finding of hemoglobin distribution of men and the test performance of anemia (Hb < 120 g/L) for detecting iron deficiency for women, it is concluded that there is no need to develop different cut-off points for anemia as a tool for iron-deficiency screening in this population.     

Community-based research: cost of the tests used for anti-HBc total seropositivity only and hepatitis B screening

Our study aimed to determine anti-HBc total (IgG+IgM) seroprevalence in the adult population aged ≥15 and to compare the cost of testing for HBsAg and anti-HBs in only anti-HBc positive (+) subpopulation to that in the whole population for HBV screening. The study involved a face-to-face survey and peripheral blood sampling from 452 adult subjects for HBV tests. HBV-DNA PCR was studied only in anti-HBc(+)subjects. Of the 452 subjects anti-HBc total was positive in 192 (42.47%), of which: (a) 27 (14.06%) were HBsAg(+), anti-HBs negative (-), (b) 126 (65.62%) were HBsAg(-), anti-HBs(+), (c) 39 were HBsAg(-), anti-HBs(-). This last group (c) were tested for HBV-DNA PCR and six (15.38%) were positive. When we perform HBsAg and anti-HBs tests in all 452 subjects as in routine practice in blood banks, the cost is 3320 Euros. However, when all subjects are tested for anti-HBc total at first and then only anti-HBc total(+) ones are tested for HBsAg and anti-HBs, the cost is 2929 Euros. The cost difference between the two methods is 391 Euros for 452 subjects. Accordingly, our HBV screening algorithm brings a financial saving of 11.78% and helps to identify the isolated anti-HBc total(+) subjects who carry potential risk for spreading HBV.     

Adaptation of multiple logistic regression to a multiple inverse sampling design: application to the Isfahan healthy heart program

In observational and experimental studies in the health sciences involving human populations, it is sometimes considered desirable to recruit subjects according to designs that specify a predetermined number of subjects in each of several mutually exclusive classes (generally but not necessarily demographic in nature). This type of adaptive sampling design, now generally referred to as multiple inverse sampling (MIS), has received recent attention, and estimation methods are now available for several sequential MIS sampling designs. In this class of designs, subjects are sampled randomly and sequentially, usually one at a time, until all classes have the pre-specified number of subjects. In this paper, we extend MIS for finite population sampling to estimation of the parameters in multiple logistic regression under MIS. Using estimated logistic regression parameters and cost components obtained from the Isfahan Healthy Heart Program (IHHP), we report findings from a simulation experiment in which it appears that, at fixed cost, MIS at the last stage of sampling compares favourably to simple random sampling. The IHHP is a large community intervention study for prevention of cardiovascular disease being conducted in Isfahan, Iran and two other cities in Iran. The IHHP identified subjects through a multistage sample survey in which MIS was used at the final stage of sampling. MIS is one of several methods of adaptive sampling that are generating considerable interest and show promise of being useful in a wide variety of applications.     

Exposure density sampling: Dynamic matching with respect to a time-dependent exposure

Estimating the potential risk associated with an exposure occurring over time requires complex statistical techniques, since ignoring the time from study entry until the exposure leads to potentially seriously biased effect estimates. A prominent example is estimating the effect of hospital-acquired infections on adverse outcomes in patients admitted to the intensive care unit. Exposure density sampling has been proposed as an approach to dynamic matching with respect to a time-dependent exposure. Firstly, exposure density sampling can be useful to reduce the workload of study follow up, as it includes all exposed but only a subset of the not yet exposed individuals. Secondly, it can help to obtain a comparable control group by including propensity score matching. In the present article, we provide the theoretical justification that data obtained by exposure density sampling can be analyzed as a left-truncated cohort. It is shown that exposure density sampling allows estimation of the effect of a time-dependent exposure as well as further baseline covariates on a subsequent event, with only minor loss in precision as compared with a full cohort analysis. The sampling is applied to a real data example (hospital-acquired infections in intensive care units) and in a simulation study. We also provide an estimate of the loss in precision in terms of an increased standard error in the reduced data set after exposure density sampling as compared with the full cohort.     

Reconstructing exposures from small samples using physiologically based pharmacokinetic models and multiple biomarkers

This study examines the use of physiologically based pharmacokinetic (PBPK) models for inferring exposure when the number of biomarker observations per individual is limited, as commonly occurs in population exposure surveys. The trade-off between sampling multiple biomarkers at a specific time versus fewer biomarkers at multiple time points was investigated, using a simulation-based approach based on a revised and updated chlorpyrifos PBPK model originally published. Two routes of exposure, oral and dermal, were studied as were varying levels of analytic measurement error. It is found that adding an additional biomarker at a given time point adds substantial additional information to the analysis, although not as much as the addition of another sampling time. Furthermore, the precision of the estimates of exposed dose scaled approximately with the analytic precision of the biomarker measurement. For acute exposure scenarios such as those considered here, the results of this study suggest that the number of biomarkers can be balanced against the number of sampling times to obtain the most efficient estimator after consideration of cost, intrusiveness, and other relevant factors.     

Prevalence and predictors of residential health hazards: a pilot study

This article reports the results of a pilot study designed to ascertain the prevalence of lead-based paint (LBP), vermin, mold, and safety conditions and hazards and to validate observations and self-reports against environmental sampling data. Data are based on a convenience sample of 70 dwellings in a low-income, urban neighborhood in Brooklyn, New York. The vast majority of residences (96%) contained multiple conditions and/or hazards: LBP hazards (80%), vermin (79%), elevated levels of airborne mold (39%), and safety hazards (100%). Observations and occupant reports were associated with environmental sampling data. In general, the more proximate an observed condition was to an actual hazard, the more likely it was to be associated with environmental sampling results (e.g., peeling LBP was associated with windowsill dust lead levels, and cockroach sightings by tenants were associated with Blatella germanica [Bla g 1] levels). Conversely, the more distal an observed condition was to an actual hazard, the less likely it was to be associated with environmental sampling results (e.g., water damage, alone, was not statistically associated with elevated levels of dust lead, Bla g 1, or airborne mold). Based on the findings from this pilot study, there is a need for industrial hygienists and others to adopt more comprehensive and integrative approaches to residential hazard assessment and remediation. Further research--using larger, randomly drawn samples, representing a range of housing types and geographical areas--is needed to clarify the relationship between readily observable conditions, occupant reports, and environmental sampling data and to assess the cumulative impact on human health.     

Effects of different sampling points on evaluation of fetal descending aortic flow

BACKGROUND: Widespread use of fetal aortic blood flow velocity measurements for assessment of fetal circulatory status has been precluded by difficulties in achieving an adequate Doppler insonation angle at particular sampling points. The goal of this study was to evaluate the differences in resistance index (RI) and systolic peak velocity (Vmax) of fetal aortic blood flow velocity waveforms throughout gestation among various Doppler sampling points. METHODS: A total of 551 normal women between 18-41 weeks of pregnancy participated in this study. Pulsed Doppler flow velocity waveforms were acquired from three different aortic sampling points (thoracic portion, beneath the diaphragm, and abdominal portion) of the fetal descending aorta. The Vmax and RI were calculated at the respective sampling points. RESULTS: The Vmax were significantly lower in abdominal portion than those in thoracic portion at every time point (from 69 +/- 11 cm/second in thoracic to 49 +/- 8 cm/second in abdominal portion at 18-19 gestational weeks, p<0.0001), and RI were also lower (from 0.84 +/- 0.05 in thoracic portion to 0.76 +/- 0.05 in abdominal portion at 18-19 gestational weeks, p<0.0001). Significant increase in the Vmax was seen until third trimester (from 58+/-10 cm/second at 18-19 gestational weeks to 113 +/- 13 cm/second at 38-39 gestational weeks beneath the diaphragm, p<0.0001), while the RI remained stable (0.79 +/- 0.04 at 18-19 gestational weeks; 0.80 +/- 0.05 at 38-39 gestational weeks beneath the diaphragm). CONCLUSIONS: In measuring the fetal circulatory status, these data demonstrate that the sampling point should be considered when evaluating the maximum systolic velocity and the resistance index of the fetal descending aorta.     

Estimating interaction between genetic and environmental risk factors: efficiency of sampling designs within a cohort

Large prospective cohorts originally assembled to study environmental risk factors are increasingly exploited to study gene-environment interactions. Given the cost of genetic studies in large samples, being able to select a subsample for genotyping that contains most of the information from the cohort would lead to substantial savings. We consider nested case-control and case-cohort sampling designs with and without stratification and compare their efficiency relative to the entire cohort for estimating the effects of genetic and environmental risk factors and their interactions. Asymptotic calculations show that the relative efficiency of the case-cohort and nested case-control designs implementing the same sampling stratification are similar over a range of scenarios for the relationships among genes, environmental exposures, and disease status. Sampling equal numbers of exposed and unexposed subjects improves efficiency when the exposure is rare. The case-cohort designs had a slight advantage in simulations of sampling designs within the Framingham Offspring Study, using the interaction between apolipoprotein E and smoking on the risk of coronary heart disease as an example. It was possible to estimate the interaction effect with precision close to that of the full cohort when using case-cohort or nested case-control samples containing fewer than half the subjects of the cohort.     

经阴道彩色多普勒超声预测药物流产不全及干预效果的探讨

目的:探讨多普勒超声早期预测药物流产不全的敏感指标及高危病例的干预措施。方法:对196例使用药物终止妊娠的健康妇女,在其孕囊排出当天使用经阴道彩色多普勒超声检测其孕囊着床部位的血流信号及螺旋动脉阻力指数(RI),进而选择早期预测药物流产不全的最佳RI值。再对358例进行药物流产的健康妇女通过预测值获取药物流产不全高危者60例随机分为两组,流产后分别加服米非司酮(米非司酮治疗组)、生化汤(生化汤治疗组)各30例,观察比较两组药物流产结局。结果:196例药物流产妇女中,完全流产者(167例)孕囊排出当天着床部位血流信号消失或螺旋动脉RI值显著增大(P<0.01),不完全流产者(29例)的RI值变化不显著(P>0.05),孕囊排出当天RI值<0.6预测药物流产不全可能的准确率为96.43%。经过对RI值<0.6的60例高危病例干预,米非司酮治疗组完全流产率(63.3%)高于生化汤治疗组(13.3%)(P<0.01)。结论:采用经阴道彩色多普勒超声可对药物流产不全进行早期预测,当RI值<0.6时,可视为高危药物流产不全,在药物流产后增服米非司酮能有效减少流产不全的发生。     

Accommodation of additional non-randomly sampled cases in a study of Helicobacter pylori infection in families

Epidemiological studies with two-stage designs typically gather information about some covariates from all study subjects in the first sampling stage, while additional data from only a subset of the subjects are collected in the second sampling stage. Appropriate analysis of two-stage studies maintains validity and can also improve precision. We describe an application of a weighted likelihood method, mean-score logistic regression, to accommodate data from a cross-sectional study of Helicobacter pylori infection in children, where the study sample was enriched with additional non-randomly sampled cases. The present work exemplifies how careful analysis of epidemiological data from complex sampling schemes can adjust for potential selection bias, improve precision and enable a more complete investigation of factors of interest. Our results highlight the importance of H. pylori infected mothers and siblings as risk factors for the infection in children in Sweden.     

Sampling Patients Within and Across Health Care Providers: Multi-Stage Non-Nested Samples in Health Services Research

In order to better inform study design decisions when sampling patients within and across health care providers we develop a simulation-based approach for designing complex multi-stage samples. The approach explores the tradeoff between competing design goals such as precision of estimates, coverage of the target population and cost.We elicit a number of sensible candidate designs, evaluate these designs with respect to multiple sampling goals, investigate their tradeoffs, and identify the design that is the best compromise among all goals. This approach recognizes that, in the practice of sampling, precision of the estimates is not the only important goal, and that there are tradeoffs with coverage and cost that should be explicitly considered. One can easily add other goals. We construct a sample frame with all phase III clinical cancer treatment trials that are conducted by cooperative oncology groups of the National Cancer Institute from October 1, 1998 through December 31, 1999. Simulation results for our study suggest sampling a different number of trials and institutions than initially considered.Simulations of different study designs can uncover efficiency gains both in terms of improved precision of the estimates and in terms of improved coverage of the target population. Simulations enable us to explore the tradeoffs between competing sampling goals and to quantify these efficiency gains. This is true even for complex designs where the stages are not strictly nested in one another.     

Generalizability of causal inference in observational studies under retrospective convenience sampling

Many observational studies adopt what we call retrospective convenience sampling (RCS). With the sample size in each arm prespecified, RCS randomly selects subjects from the treatment‐inclined subpopulation into the treatment arm and those from the control‐inclined into the control arm. Samples in each arm are representative of the respective subpopulation, but the proportion of the 2 subpopulations is usually not preserved in the sample data. We show in this work that, under RCS, existing causal effect estimators actually estimate the treatment effect over the sample population instead of the underlying study population. We investigate how to correct existing methods for consistent estimation of the treatment effect over the underlying population. Although RCS is adopted in medical studies for ethical and cost‐effective purposes, it also has a big advantage for statistical inference: When the tendency to receive treatment is low in a study population, treatment effect estimators under RCS, with proper correction, are more efficient than their parallels under random sampling. These properties are investigated both theoretically and through numerical demonstration.     

Factors affecting the accuracy of airborne quartz determination

Samples collected in a foundry were used to analyze sources of variation and factors influencing the overall accuracy of sampling results. Air samples were analyzed by Fourier Transform Infrared Spectroscopy (FTIR) using NIOSH Method 7602 to study particle size effects, analytical precision, sampling equipment performance, and production factors. The FTIR technique provides accuracy when silica particle size is taken into consideration. In this case, the variability due to analytical factors is small compared with other sources of error. The typical coefficient of variation of the analytical procedure is 0.08; variation associated with sampling reaches 0.21; and interday coefficient of variation can be as high as 0.48. The IR method has advantages over XRD analysis, including cost effectiveness, sensitivity, and a lower detection limit.     

浙江省部分在校大学生对电子烟的态度及其影响因素

  目的  了解浙江省大学生对电子烟的态度及其影响因素,为制定大学生电子烟防控策略提供依据。  方法  采用典型抽样和方便抽样结合的方法,于2020年9月选取浙江省不同类型本、专科院校共10所,通过发放电子问卷进行在线调查,采用多因素Logistic回归模型分析大学生对电子烟态度的影响因素。  结果  884名被试中,93名(10.52%)对电子烟持支持态度,310名(35.07%)认为电子烟无害,252名(28.51%)认为电子烟不会上瘾; 67名(7.58%)正在使用电子烟。多因素Logistic回归分析结果表明,性别、年级、生活费、是否吸电子烟和是否认为电子烟有害对在校大学生对电子烟态度的影响均有统计学意义(OR值分别为0.59,0.47,1.87,0.34,0.54,P值均＜0.05)。  结论  浙江省在校大学生对电子烟持较为支持的态度,对其危害认识不充分。在面向大学生群体的控烟工作中,应着力破除电子烟的正面形象,在干预人群上特别重视低年级大学生,同时不能忽视女大学生群体。     

卫生专业技术人员职业紧张调查分析

目的:通过对卫生专业技术人员职业紧张状况进行调查分析,制定干预措施,为降低职业紧张提供相应对策。方法:随机整群抽取宝安区某街道卫生专业技术人员96人,采用职业紧张量表评价其职业紧张水平。结果:职业任务问卷中子项目任务不适和任务模糊得分,紧张反应问卷中子项目业务紧张反应、心理紧张反应和躯体紧张反应得分,个人资源问卷中子项目娱乐休闲和自我保健得分,均高于常模;职业任务问卷中子项目工作环境得分和个人资源问卷中子项目理性处事得分,均低于常模;业务紧张反应与任务不适、自我保健,人际紧张反应与自我保健、社会支持,以及躯体紧张反应与任务不适的相关性,差异无统计学意义(P>0.05),紧张反应与职业任务成正相关,紧张反应与个人资源成负相关。结论:该人群职业紧张水平较高,建议通过统筹工作分配,加强人文关怀,提升个人资源,增强其对职业紧张的应对能力。     

Effect of smoking on weight and cardiopulmonary capacities in young athletes

The aim of the study was to determine wether smokers practising sports have reduced weight, if recuperation time after moderate exercise and maximal aerobic power were lowered. Thousand young soldiers [50 smokers (S), 50 no smokers (NS)] averaging 24 years in age were studied. The subjects performed to exhaustion on Ruffier test, then a maximal exercise with Cooper test. Several biometrical and physiological parameters were evaluated: weight (W), percent of body fat (PBF), body mass index (BMI), maximal oxygen uptake (VO2 max) and recuperation index (RI). Kinetics of heart rate (HR) were studied for 7 min considering time constant (1 min) and delay for recovery. The smokers showed significant differences for W (p < 0.001), PBF (p < 0.05), VO2 max (p < 0.01) and recuperation index (p < 0.001). Maximal aerobic power were 45.8 +/- 2.7 and 50.3 +/- 3.2 ml/kg/min for S and NS, and RI were 7.5 +/- 0.9 (S) and 5.0 +/- 1 (NS). figure 1 shows that HR recovery of S has generally two components: the first was fast, the second was a slone none. The smokers who presented a great dependence to tobacco smoking had a significant lower RI (p < 0.001) as those subjects with little tobacco dependence (Table 5). The smokers had lower values of VO2 max, and there exists a tobacco dependence difference. Recuperation time for the aerobically well trained S subjects was more rapid during the lactic phase. Note that correlations obtained between the VO2 max and RI were significant (r = - 0.788; p < 0.05). The smokers and no smokers differences are discussed with reference to nicotinemia effects and the sympathetic-parasympathetic unbatance of influences. The comparison of smokers groups concerning cardiovascular data led to suppose that there exists a tobacco dependence difference in regards of the catecholaminergic sensitivity. In conclusion, this study showed that smoker practising a physical activity have a reduced weight, a higher recuperation time and an anaerobic limitation influenced by the state of tobacco dependence.     

Cost-effectiveness of type 2 diabetes screening: results from recently published studies

Type 2 diabetes screening is recommended by various international diabetes associations. We conducted a literature research to identify and describe systematically recently published cost effectiveness analyses (CEA) for type 2 diabetes screening. Three analyses were included. One of them was conducted in Germany, based on the data of the KORA survey S4 (1999/2001). Two studies came from the US. The German as well as one of the US studies evaluated cost per detected diabetic case as main outcome. In contrast to the US study, the German study considered incomplete participation in the screening programs as baseline case. HbA1 c testing combined with the oral glucose tolerance test (OGTT) was more expensive than OGTT or fasting glucose testing, but also most effective in detecting cases, due to high participation in this screening strategy. The second US study investigated the lifetime cost effectiveness of type 2 diabetes screening, based on a Markov model to calculate cost per quality-adjusted life year (QALY). Effectiveness data were derived from two large intervention studies in clinically diagnosed (not identified by screening) diabetic subjects. The authors conclude that type 2 diabetes screening is cost effective, in particular targeted screening in elderly hypertensive subjects. Diabetes screening may be cost effective. However, the effectiveness of early detection and treatment of type 2 diabetes has not yet been shown, and data regarding the course of early detected diabetes are lacking so far. In the future, the most important question is whether type 2 diabetes screening and early treatment is effective with respect to clinical outcomes.     

Validity Testing the Outcomes and Assessment Information Set (OASIS)

This study evaluated the criterion validity of the Outcome and Assessment Instrument Set (OASIS) items that measure activities of daily living (ADLs), instrumental activities of daily living (IADLs), cognitive functioning, and depression. A convenience sample of patients (n?=?203) from five home care agencies participated in the study. Patient OASIS items were compared to data collected using gold standard instruments. Correlations range from .44 to .69 for ADLs and .20 to .68 for IADLs. A correlation of .62 was found for cognitive functioning while correlations for depressive symptoms are .36 and .26. OASIS ADLs and cognitive status items are sufficiently valid, but the OASIS depression item is not sufficiently sensitive to the prevalence of these conditions.