Manual and Semi-Automated Measurement and Calculation of Osteosarcoma Treatment Effect Using Whole Slide Image and Qupath.

INTRODUCTION: In osteosarcoma, the most significant indicator of prognosis is the histologic changes related to tumor response to preoperative chemotherapy, such as necrosis. We have developed a method to measure the osteosarcoma treatment effect using whole slide image (WSI) with an open-source digital image analytical software Qupath. MATERIALS AND METHODS: In Qupath, each osteosarcoma case was treated as a project. All H&E slides from the entire representative slice of osteosarcoma were scanned into WSIs and imported into a project in Qupath. The regions of tumor and tumor necrosis were annotated, and their areas were measured in Qupath. In order to measure the osteosarcoma treatment effect, we needed to calculate the percentage of total necrosis area over total tumor area. We developed a tool that can automatically extract all values of tumor and necrosis areas from a Qupath project into an Excel file, sum these values for necrosis and whole tumor respectively, and calculate necrosis/tumor percentage. CONCLUSION: Our method that combines WSI with Qupath can provide an objective measurement to facilitate pathologist's assessment of osteosarcoma response to treatment. The proposed approach can also be used for other types of tumors that have clinical need for post-treatment response assessment.

Fixed and random effect selections in generalized linear mixed models.

Generalized linear mixed models are commonly used to describe relationships between correlated responses and covariates in medical research. In this paper, we propose a simple and easily implementable regularized estimation approach to select both fixed and random effects in generalized linear mixed model. Specifically, we propose to construct and optimize the objective functions using the confidence distributions of model parameters, as opposed to using the observed data likelihood functions, to perform effect selections. Two estimation methods are developed. The first one is to use the joint confidence distribution of model parameters to perform simultaneous fixed and random effect selections. The second method is to use the marginal confidence distributions of model parameters to perform the selections of fixed and random effects separately. With a proper choice of regularization parameters in the adaptive LASSO framework, we show the consistency and oracle properties of the proposed regularized estimators. Simulation studies have been conducted to assess the performance of the proposed estimators and demonstrate computational efficiency. Our method has also been applied to two longitudinal cancer studies to identify demographic and clinical factors associated with patient health outcomes after cancer therapies.

Multivariate survival analysis in big data: A divide-and-combine approach.

Multivariate failure time data are frequently analyzed using the marginal proportional hazards models and the frailty models. When the sample size is extraordinarily large, using either approach could face computational challenges. In this paper, we focus on the marginal model approach and propose a divide-and-combine method to analyze large-scale multivariate failure time data. Our method is motivated by the Myocardial Infarction Data Acquisition System (MIDAS), a New Jersey statewide database that includes 73,725,160 admissions to nonfederal hospitals and emergency rooms (ERs) from 1995 to 2017. We propose to randomly divide the full data into multiple subsets and propose a weighted method to combine these estimators obtained from individual subsets using three weights. Under mild conditions, we show that the combined estimator is asymptotically equivalent to the estimator obtained from the full data as if the data were analyzed all at once. In addition, to screen out risk factors with weak signals, we propose to perform the regularized estimation on the combined estimator using its combined confidence distribution. Theoretical properties, such as consistency, oracle properties, and asymptotic equivalence between the divide-and-combine approach and the full data approach are studied. Performance of the proposed method is investigated using simulation studies. Our method is applied to the MIDAS data to identify risk factors related to multivariate cardiovascular-related health outcomes.

Preeclamptic Women Are at Significantly Higher Risk of Future Cardiovascular Outcomes Over a 15-Year Period.

Background: Preeclampsia (PE) may lead to maternal and infant mortality and severe medical complications. Understanding future short- and long-term cardiovascular (CV) outcomes of PE is important to women's health. Materials and Methods: A retrospective matched case-control study assessed the risks of CV outcomes over a 15-year period (1999-2013) in pregnant case women, with gravidity and parity of one, diagnosed with PE, compared to pregnant primiparous control women who were not diagnosed with PE. The New Jersey Electronic Birth Certificate (EBC) database and the Myocardial Infarction Data Acquisition System (MIDAS), a database of all hospital admissions in New Jersey with longitudinal follow-up, were used to conduct the analysis. Participants were 18 years and older with demographics consistent with New Jersey, a state with a range of racial and ethnic diversity. Main outcome measures postpregnancy and over this 15-year period were myocardial infarction (MI), stroke, CV death, and all-cause death. Results: Women with PE (N = 6,360) were more likely to suffer MI, stroke, CV death, and all-cause death than controls (N = 325,347). After matching cases to controls for demographics and comorbidities, hazard ratios of PE cases for the outcomes of MI (p adjusted for comorbidities and demographics = 0.0196), CV death (adjusted p = 0.007), and all-cause death (adjusted p = 0.0026) were significantly higher than 1 compared to matched controls. Women with PE had 3.94 (95% CI: 1.25-12.4) times higher hazard for MI, 4.66 (95% CI: 1.52-14.26) times higher hazard of CV death, and 2.32 (95% CI: 1.34-4.02) times higher hazard for all-cause death than matched controls. Conclusions: This 15-year study indicates that women who have PE with their first pregnancy have a significantly higher risk of adverse CV outcomes compared to controls and suggest a heightened and continued CV monitoring after birth for this population of women.

Pollen magnetofection for genetic modification with magnetic nanoparticles as gene carriers.

Genetic modification plays a vital role in breeding new crops with excellent traits. Almost all the current genetic modification methods require regeneration from tissue culture, involving complicated, long and laborious processes. In particular, many crop species such as cotton are difficult to regenerate. Here, we report a novel transformation platform technology, pollen magnetofection, to directly produce transgenic seeds without regeneration. In this system, exogenous DNA loaded with magnetic nanoparticles was delivered into pollen in the presence of a magnetic field. Through pollination with magnetofected pollen, transgenic plants were successfully generated from transformed seeds. Exogenous DNA was successfully integrated into the genome, effectively expressed and stably inherited in the offspring. Our system is culture-free and genotype independent. In addition, it is simple, fast and capable of multi-gene transformation. We envision that pollen magnetofection can transform almost all crops, greatly facilitating breeding processes of new varieties of transgenic crops.

Ischemic Stroke Rate Increases in Young Adults: Evidence for a Generational Effect?

BACKGROUND: The incidence rates of ischemic stroke and ST-segment elevation myocardial infarction (STEMI) have decreased significantly in the United States since 1950. However, there is evidence of flattening of this trend or increasing rates for stroke in patients younger than 50 years. The objective of this study was to examine the changes in incidence rates of stroke and STEMI using an age-period-cohort model with statewide data from New Jersey. METHODS AND RESULTS: We obtained stroke and STEMI data for the years 1995-2014 from the Myocardial Infarction Data Acquisition System, a database of hospital discharges in New Jersey. Rates by age for the time periods 1994-1999, 2000-2004, 2005-2009, and 2010-2014 were obtained using census estimates as denominators for each age group and period. The rate of stroke more than doubled in patients aged 35 to 39 years from 1995-1999 to 2010-2014 (rate ratio [RR], 2.47; 95% CI, 2.07-2.96 [P<0.0001]). We also found increased rates of stroke in those aged 40 to 44, 45 to 49, and 50 to 54 years. Strokes rates in those older than 55 years decreased during these time periods. Those born from 1945-1954 had lower age-adjusted rates of stroke than those born both in the prior 20 years and in the following 20 years. STEMI rates, in contrast, decreased in all age groups and in each successive birth cohort. CONCLUSIONS: There appears to be a significant birth cohort effect in the risk of stroke, where patients born from 1945-1954 have lower age-adjusted rates of stroke compared with those born in earlier and later years.

Experience With Anti-TNF-α Biologic Agents in Succession in Patients With Crohn's Disease: A Retrospective Analysis of a Single Center.

GOALS: Our aim was to identify and compare the effectiveness of antitumor necrosis factor biologics when used as initial agents and when used in succession for the treatment of moderate to severe Crohn's disease (CD). BACKGROUND: Studies directly comparing the efficacy of biologics are lacking. When one biologic loses efficacy, patients are often treated with an alternate biologic. The effectiveness of this strategy has not been thoroughly investigated. STUDY: This is a retrospective cohort study from a database of 153 patients with CD treated with infliximab, adalimumab, or certolizumab pegol. Response rates determined by physician global assessment were compared between biologics when given as initial agents and after failure of 1 or 2 prior biologics. RESULTS: There were no significant differences in response between infliximab (64.5%), adalimumab (60.0%), and certolizumab pegol (66.7%) when given as initial biologics. As second-line or third-line agents after prior biologic failure, there was a trend toward increased response with infliximab (83.3%) versus adalimumab (52.7%) and certolizumab pegol (59.4%); however, this did not meet statistical significance. After failure or loss of response of 2 previous biologics, use of a third biologic was still effective with a response rate of 54.2%. CONCLUSIONS: All 3 biologics have similar efficacy in the treatment of CD when given as initial agents. Infliximab has a trend toward increased response after prior biologic failure; however, this did not meet statistical significance. Even after loss of response or failure of 2 previous biologics, trial of a third alternate biologic is an effective strategy.

Usefulness of a normal coronary angiogram in patients aged ≥65 years to foretell survival.

A normal coronary angiogram (CA) has been reported to confer a good prognosis. However, how this applies to patients aged ≥65 years is not well known. From 1986 to 1996, 11,625 patients aged ≥65 underwent coronary angiography. We identified 271 patients with either normal (NORM, n = 160) CA or <30% diameter stenosis disease (NEAR-NORM, n = 111). Using the Myocardial Infarction Data Acquisition System, we examined the probability of survival and the risk of developing an ischemic event or undergoing a revascularization procedure during an average of 15.1 ± 6.2 years (range 0.5 to 25.8 years). Matched actuarial subjects were used to compare survival to the general population. The incidence of an ischemic event was low (2.0 events per 100 persons/year for the NORM and 2.8 patients per 100 persons/year for the NEAR-NORM group, p = NS). Rates of revascularization were higher in the NEAR-NORM group compared to the NORM group (1 per 100 persons/year vs 0.5 per 100 persons/year, p = 0.04). During the 25.8-year follow-up, there were 77 deaths (48.4%) for the NORM and 64 (57.1%) for the NEAR-NORM group (χ2 = 1.7, NS). The NORM group survived 6,789 days, 1,517 more days than the actuarial subjects (95% confidence interval [CI] 1,072 to 1,956; p <0.0001) and the NEAR-NORM group survived 5,922 days, 875 more days (95% CI 368 to 1,376; p <0.005). In conclusion, patients with normal or near-normal CA at age ≥65 years have a low rate of myocardial ischemic events and have significantly longer survival than matched subjects from the general population.

Comprehensive stroke centers may be associated with improved survival in hemorrhagic stroke.

BACKGROUND: Comprehensive stroke centers (CSCs) provide a full spectrum of neurological and neurosurgical services to treat complex stroke patients. CSCs have been shown to improve clinical outcomes and mitigate disparities in ischemic stroke patients. It is believed that CSCs also improve outcomes in hemorrhagic stroke. METHODS AND RESULTS: We used the Myocardial Infarction Data Acquisition System (MIDAS) database, which includes data on patients discharged with a primary diagnosis of intracerebral hemorrhage (ICH; International Classification of Diseases, Ninth Revision [ICD-9] 431) and subarachnoid hemorrhage (SAH; ICD-9 430) from all nonfederal acute care hospitals in New Jersey (NJ) between 1996 and 2012. Out-of-hospital deaths were assessed by matching MIDAS records with NJ death registration files. The primary outcome variable was 90-day all-cause mortality. The primary independent variable was CSC versus primary stroke center (PSC) and nonstroke center (NSC) admission. Multivariate logistic models were used to measure the effects of available covariates. Overall, 36 981 patients were admitted with a primary diagnosis of ICH or SAH during the study period, of which 40% were admitted to a CSC. Patients admitted to CSCs were more likely to have neurosurgical or endovascular interventions than those admitted to a PSC/NSC (18.9% vs. 4.7%; P<0.0001). CSC admission was associated with lower adjusted 90-day mortality (35.0% vs. 40.3%; odds ratio, 0.93; 95% confidence interval, 0.89 to 0.97) for hemorrhagic stroke. This was particularly true for those admitted with SAH. CONCLUSIONS: Hemorrhagic stroke patients admitted to CSCs are more likely to receive neurosurgical and endovascular treatments and be alive at 90 days than patients admitted to other hospitals.

Erectile Dysfunction Is Common among Patients with Gout.

OBJECTIVE: To determine whether men with gout may have an increased prevalence of erectile dysfunction (ED) as compared with men without gout. METHODS: In this cross-sectional study, men aged 18-89 presenting to the rheumatology clinic between August 26, 2010, and May 13, 2013, were asked to participate. The presence of ED was determined by the Sexual Health Inventory in Men (SHIM). SHIM classifies ED into 1 of 5 categories: absent (22-25), mild (17-21), mild to moderate (12-16), moderate (8-11), and severe (1-7). Patient's history, physical examination, and recent laboratory studies were reviewed as well. Descriptive statistics and subgroup analyses were used to summarize the data. RESULTS: Of the 201 men surveyed, 83 had gout (control, n = 118). A significantly greater proportion of patients with gout (63, 76%) had ED versus patients without gout (60, 51%, p = 0.0003). A significantly greater proportion of patients with gout (22, 26%) had severe ED versus patients without gout (17, 15%, p = 0.04). Patients with gout had an average SHIM score of 14.4 versus 18.48 in patients without gout (p < 0.0001). There was a statistically significant association between gout and ED. The association remained significant after adjustment for age, hypertension, diabetes, and obesity. CONCLUSION: ED is present in most men with gout and is frequently severe. We propose that patients with gout be routinely screened for ED.

Competing cardiovascular and noncardiovascular risks and longevity in the systolic hypertension in the elderly program.

We examined the effect of chlorthalidone-based stepped care on the competing risks of cardiovascular (CV) versus non-CV death in the Systolic Hypertension in the Elderly Program (SHEP). Participants were randomly assigned to chlorthalidone-based stepped-care therapy (n = 2,365) or placebo (n = 2,371) for 4.5 years, and all participants were advised to take active therapy thereafter. At the 22-year follow-up, the gain in life expectancy free from CV death in the active treatment group was 145 days (95% confidence interval [CI] 23 to 260, p = 0.012). The gain in overall life expectancy was smaller (105 days, 95% CI -39 to 242, p = 0.073) because of a 40-day (95% CI -87 to 161) decrease in survival from non-CV death. Compared with an age- and gender-matched cohort, participants had markedly higher overall life expectancy (Wilcoxon p = 0.00001) and greater chance of reaching the ages of 80 (81.3% vs 57.6%), 85 (58.1% vs 37.4%), 90 (30.5% vs 22.0%), 95 (11.9% vs 8.8%), and 100 years (3.7% vs 2.8%). In conclusion, Systolic Hypertension in the Elderly Program participants had higher overall life expectancy than actuarial controls and those randomized to active therapy had longer life expectancy free from CV death but had a small increase in the competing risk of non-CV death.

Large-scale parametric survival analysis.

Survival analysis has been a topic of active statistical research in the past few decades with applications spread across several areas. Traditional applications usually consider data with only a small numbers of predictors with a few hundreds or thousands of observations. Recent advances in data acquisition techniques and computation power have led to considerable interest in analyzing very-high-dimensional data where the number of predictor variables and the number of observations range between 10(4) and 10(6). In this paper, we present a tool for performing large-scale regularized parametric survival analysis using a variant of the cyclic coordinate descent method. Through our experiments on two real data sets, we show that application of regularized models to high-dimensional data avoids overfitting and can provide improved predictive performance and calibration over corresponding low-dimensional models.

Relationships between selected gene polymorphisms and blood pressure sensitivity to weight loss in elderly persons with hypertension.

Salt sensitivity, the heterogeneity in the response of blood pressure (BP) to alterations in sodium intake, has been studied extensively, whereas weight sensitivity, the heterogeneity in BP response to weight change, has received scant attention. We examined the relationship of 21 gene polymorphisms previously found to be associated with hypertension, diabetes mellitus, or obesity, with weight sensitivity in the Trial of Nonpharmacologic Interventions in the Elderly, where participants with hypertension were randomized to receive intensive dietary intervention of sodium reduction, weight loss, both, or attention control, whereas pharmacological therapy was kept constant. After correcting for multiplicity, we identified significant associations of 3 polymorphisms with weight sensitivity of systolic BP (rs4646994, rs2820037, and rs1800629) and 3 polymorphisms for diastolic BP (rs4646994, rs2820037, and rs5744292). A recursive partitioning algorithm selected the combination of rs4646994, rs1800629, rs1982073, and rs1800896 as the set associated with the highest weight sensitivity. Polymorphisms related to hypertension, obesity, and diabetes mellitus are associated with weight sensitivity of BP.

Meta-analysis of statin effects in women versus men.

OBJECTIVES: The aim of this study was to evaluate the effect of statins in decreasing cardiovascular events in women and men. BACKGROUND: Published data reviews have suggested that statins might not be as effective in women as in men in decreasing cardiovascular events. METHODS: Published data searches and contacts with investigators identified 18 randomized clinical trials of statins with sex-specific outcomes (N = 141,235, 40,275 women, 21,468 cardiovascular events). Odds ratios (ORs) and 95% confidence intervals (CIs) for cardiovascular events were calculated for women and men separately with random effects meta-analyses. RESULTS: The cardiovascular event rate was lower among those randomized to statin intervention than in those randomized to control (low-dose statin in 4 studies, placebo in 11 studies, usual care in 3 studies) and similar in women and men (OR: 0.81, 95% CI: 0.75 to 0.89; p < 0.0001, and OR: 0.77, 95% CI: 0.71 to 0.83, p < 0.0001, respectively). The benefit of statins was statistically significant in both sexes, regardless of the type of control, baseline risk, or type of endpoint and in both primary and secondary prevention. All-cause mortality was also lower with statin therapy both in women and men without significant interaction by sex (p for interaction = 0.4457). CONCLUSIONS: Statin therapy is associated with significant decreases in cardiovascular events and in all-cause mortality in women and men. Statin therapy should be used in appropriate patients without regard to sex.

Association between chlorthalidone treatment of systolic hypertension and long-term survival.

CONTEXT: In the Systolic Hypertension in the Elderly Program (SHEP) trial, conducted between 1985 and 1990, antihypertensive therapy with chlorthalidone-based stepped-care therapy resulted in a lower rate of cardiovascular events than placebo but effects on mortality were not significant. OBJECTIVE: To study the gain in life expectancy of participants randomized to active therapy at the 22-year follow-up. DESIGN, SETTING, AND PARTICIPANTS: A National Death Index ascertainment of death in the long-term follow-up of a randomized, placebo-controlled, clinical trial (SHEP) of patients aged 60 years or older with isolated systolic hypertension. Recruitment was between March 1, 1985, and January 15, 1988. After the end of a 4.5-year randomized phase of the SHEP trial, all participants were advised to receive active therapy. The time interval between the beginning of recruitment and the ascertainment of death by National Death Index (December 31, 2006) was approximately 22 years (21 years 10 months). MAIN OUTCOME MEASURES: Cardiovascular death and all-cause mortality. RESULTS: At the 22-year follow-up, life expectancy gain, expressed as the area between active (n = 2365) and placebo (n = 2371) survival curves, was 105 days (95% CI, -39 to 242; P = .07) for all-cause mortality and 158 days (95% CI, 36-287; P = .009) for cardiovascular death. Each month of active treatment was therefore associated with approximately 1 day extension in life expectancy. The active treatment group had higher survival free from cardiovascular death vs the placebo group (hazard ratio [HR], 0.89; 95% CI, 0.80-0.99; P = .03) but similar survival for all-cause mortality (HR, 0.97; 95% CI, 0.90-1.04; P = .42). There were 1416 deaths (59.9%) in the active treatment group and 1435 deaths (60.5%) in the placebo group (log-rank P = .38, Wilcoxon P = .24). Cardiovascular death was lower in the active treatment group (669 deaths [28.3%]) vs the placebo group (735 deaths [31.0%]; log-rank P = .03, Wilcoxon P = .02). Time to 70th percentile survival was 0.56 years (95% CI, -0.14 to 1.23) longer in the active treatment group vs the placebo group (11.53 vs 10.98 years; P = .03) for all-cause mortality and 1.41 years (95% CI, 0.34-2.61; 17.81 vs 16.39 years; P = .01) for survival free from cardiovascular death. CONCLUSION: In the SHEP trial, treatment of isolated systolic hypertension with chlorthalidone stepped-care therapy for 4.5 years was associated with longer life expectancy at 22 years of follow-up.

Continuation of mortality reduction after the end of randomized therapy in clinical trials of lipid-lowering therapy.

BACKGROUND: Long-term follow-up of clinical trials with lipid-lowering medications has suggested a continuation of event reduction after study completion. OBJECTIVE: To evaluate the persistence of the benefit of lipid-lowering therapy in decreasing mortality after the end of clinical trials, when all patients were advised to take the same open-label lipid-lowering therapy. METHODS: Through searches of MEDLINE, the Cochrane Library, the Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov until June 2010 we identified randomized clinical trials of lipid-lowering agents with a second report describing results after the end of the trial. RESULTS: Among the 459 trials reviewed, only 8 including 44,255 patients and 8144 deaths qualified for the meta-analysis. All-cause and cardiovascular mortality were lower in the active intervention group during the first phase (0.84, 95% confidence interval [CI] 0.76-0.93; P = .0006 and 0.72, 95% CI 0.63-0.82, P < .0001, respectively) when 71 ± 23% of the patients randomized to receive active therapy actually received it compared with 13 ± 5% of patients who received active therapy although they were randomized to placebo (P = .0001). The lower mortality among those initially randomized to active therapy persisted during the second phase (odds ratio 0.90, 95% CI 0.84-0.97, P = .0035, and 0.82 95% CI 0.73-0.93, P = .0014), when patients in both randomized groups received active therapy in the same proportions (5 ± 2% for both groups). Numerous sensitivity analyses support the conclusions of the paper. CONCLUSION: The decrease in mortality with lipid-lowering therapy in clinical trials persists after discontinuation of randomized therapy when patients in the treatment and placebo groups receive active therapy.