Covariate measurement error in regression analysis is an important issue that has been studied extensively under the classical additive and the Berkson error models. Here, we consider cases where covariates are derived from tumor tissue histology, and in particular tissue microarrays. In such settings, biomarkers are evaluated from tissue cores that are subsampled from a larger tissue section so that these biomarkers are only estimates of the true cell densities. The resulting measurement error is non-negligible but is seldom accounted for in the analysis of cancer studies involving tissue microarrays. To adjust for this type of measurement error, we assume that these discrete-valued biomarkers are conditionally Poisson distributed, based on a Poisson process model governing the spatial locations of marker-positive cells. Existing methods for addressing conditional Poisson surrogates, particularly in the absence of internal validation data, are limited. We extend the simulation extrapolation (SIMEX) algorithm to accommodate the conditional Poisson case (POI-SIMEX), where measurement errors are non-Gaussian with heteroscedastic variance. The proposed estimator is shown to be strongly consistent in a linear regression model under the assumption of a conditional Poisson distribution for the observed biomarker. Simulation studies evaluate the performance of POI-SIMEX, comparing it with the naive method and an alternative corrected likelihood approach in linear regression and survival analysis contexts. POI-SIMEX is then applied to a study of high-grade serous cancer, examining the association between survival and the presence of triple-positive biomarker (CD3+CD8+FOXP3+ cells)

This paper considers estimation for linear regression analysis with covariate measurement error arising from Poisson surrogates. We consider cases where covariates follow a conditional Poisson distribution, capturing non-Gaussian and heteroscedastic error structures. To address this, we extend the simulation extrapolation (SIMEX) algorithm to the conditional Poisson setting (POI-SIMEX), allowing for adjustment in the absence of internal validation data. Theoretical analysis establishes the strong consistency of the POI-SIMEX estimator under a linear regression framework.

Discrete biomarkers derived as cell densities or counts from tissue microarrays and immunostaining are widely used to study immune signatures in relation to survival outcomes in cancer. Although routinely collected, these signatures are not measured with exact precision because the sampling mechanism involves examination of small tissue cores from a larger section of interest. We model these error-prone biomarkers as Poisson processes with latent rates, inducing heteroscedasticity in their conditional variance. While critical for tumor histology, such measurement error frameworks remain understudied for conditionally Poisson-distributed covariates. To address this, we propose a Bayesian joint model that incorporates a Dirichlet process (DP) mixture to flexibly characterize the latent covariate distribution. The proposed approach is evaluated using simulation studies which demonstrate a superior bias reduction and robustness to the underlying model in realistic settings when compared to existing methods. We further incorporate Bayes factors for hypothesis testing in the Bayesian semiparametric joint model. The methodology is applied to a survival study of high-grade serous carcinoma where comparisons are made between the proposed and existing approaches. Accompanying R software is available at the GitHub repository listed in the Web Appendices.

Paralytic shellfish toxins (PST) in shellfish products have led to severe risks to human health. To monitor the risk, the Canadian Shellfish Sanitation Program has been collecting longitudinal PST measurements in blue mussel (Mytilus edulis) and soft-shell clam (Mya arenaria) samples in six coastal provinces of Canada. The spatial distributions of major temporal variation patterns were studied via Functional Principal Component Analysis. Seasonal increases in PST contamination were found to vary the most in terms of magnitude along the coastlines, which provides support for location-specific management of the time-sensitive PST contamination. In British Columbia, the first functional principal component (FPC1) indicated the variance among the magnitudes, while FPC2 indicated the seasonality of the PST levels. The temporal variations tended to be positively correlated with the abundance of dianoflagellates Alexandrium spp., and negatively with precipitation and inorganic nutrients. These findings indicate the underlying mechanism of PST variation in various geographical settings. In New Brunswick, Prince Edward, and Nova Scotia, the top FPCs indicated that the PST contamination differed mostly in the seasonal increase of the PST level during summer.

Introduction: Age-related differences in the safety profile of cemiplimab for patients with locally advanced or metastatic cutaneous squamous cell carcinoma (cSCC) have not been well described. We investigated the association of increasing age with immune related adverse events (irAE) from cemiplimab, efficacy outcomes, and the prognostic significance of pre-treatment blood biomarkers in contemporary practice. Materials and methods: Patients starting first-line cemiplimab for locally advanced or metastatic cSCC at British Columbia Cancer between April 2019 and January 2023 were identified. Landmark four-month logistic regression analysis compared the odds of developing irAE or sequelae amongst patients aged <75 years to those aged 75-84 or >= 85. Objective responses were determined using Response Evaluation Criteria in Solid Tumors version 1.1. Univariable Cox proportional hazard (PH) regression modelling of factors associated with overall survival (OS) was performed. Results: Of 106 patients, the proportions aged <75, 75-84, and >= 85 years were 34%, 45%, and 21%, respectively. Overall, the proportion of patients with irAE >= grade 3, cemiplimab discontinuation, and hospitalization for immune toxicity was 27.4%, 31.1%, and 11.3%, respectively. There was no clear association between age and the odds of high grade irAE. However, increased odds of cemiplimab discontinuation was observed in patients aged 75-84 years (p = 0.05). Patients >= 85 years had increased hospitalizations due to irAE (OR = 5.00, 95% CI = 0.97-37.52) with two treatment-related deaths. Objective responses were similar across age cohorts (50.0%, 60.4%, and 54.5%) but progressive disease was higher in the age >= 85 group (22.2%, 18.8%, and 31.8%). On Cox PH regression analysis, age >= 85 years (vs. <75), Eastern Cooperative Oncology Group performance status 2-3 (vs. 0-1), and neutrophil to lymphocyte ratio (NLR) >= 7.80 (vs. <7.80) were associated with shorter survival. Discussion: While the odds of high grade irAE were similar across age groups, significant age-related differences in treatment discontinuation and hospitalization due to immune toxicity were observed. Despite a higher incidence of primary progression and shorter OS in the oldest cohort, cemiplimab yielded robust objective responses regardless of age. Higher pre-treatment NLR was associated with shorter survival and the cut-point identified requires further study.

Concurrent chemoradiotherapy (cCRT) followed by 1 year of the immune checkpoint inhibitor (ICI) durvalumab is standard of care for patients with unresectable stage III nonsmall cell lung cancer (NSCLC). The purpose of this study was to evaluate survival outcomes of (1) cCRT followed by durvalumab in patients older versus younger than 75 years of age and (2) post-progression treatment with ICI alone versus chemotherapy alone versus combined ICI and chemotherapy. Patients with unresectable stage III NSCLC treated between January 2018 and July 2023 with cCRT followed by durvalumab were identified retrospectively. Progression-free survival (PFS) and overall survival (OS) from ICI start were analyzed in three cohorts aged < 65, 65–74, and ≥ 75 years. Multivariable Cox proportional hazard regression modelling of factors associated with OS was undertaken. Logistic regression analysis identified risk factors of early durvalumab discontinuation for toxicity. Time from first salvage drug treatment to death (OS-2) was described. A total of 472 patients were analyzed: the proportions aged < 65, 65–74, and ≥ 75 years were 34.3

Shellfish poisonings have posed severe risks to human health globally. The Canadian Shellfish Sanitation Program was established in 1948 to monitor the toxin levels at shellfish harvesting sites along the coast of six provinces in Canada. Domoic acid has been a causal toxin for amnesic shellfish poisoning, and a macro-scale analysis of the temporal and spatial variation of domoic acid along Canada's coast was conducted in this study. We aggregated the toxin levels by week in blue mussel (Mytilus edulis) and soft-shell clam (Mya arenaria) samples, respectively, over a one-year scale. The subsequent application of Functional Principal Component Analysis unveiled that magnitudes of seasonal variation and peaked DA levels around early summer, spring, or mid-fall formed the largest variation in the toxin levels in blue mussels along the coastlines of British Columbia and Prince Edward Island and in soft-shell calms along those of New Brunswick and Nova Scotia. In Quebec, the DA levels were low and varied mostly in terms of the overall magnitude from spring to fall. Downstream correlation analyses in British Columbia further discovered that, at most sites, the strongest correlations were negative between precipitation as well as inorganic nutrients (including nitrate, nitrite, phosphate, and silicate) on one side and DA a few weeks afterward on the other. These findings indicated associations between amnesic shellfish poisoning and environmental stresses.

Unlike other histological types of epithelial ovarian carcinoma, clear cell ovarian carcinoma (CCOC) has poor response to therapy. In many other carcinomas, expression of the hypoxia-related enzyme Carbonic anhydrase IX (CAIX) by cancer cells is associated with poor prognosis, while the presence of CD8 + tumor-infiltrating lymphocytes (TIL) is positively prognostic. We employed [18F]EF5-PET/CT imaging, transcriptome profiling, and spatially-resolved histological analysis to evaluate relationships between CAIX, CD8, and survival in CCOC. Tissue microarrays (TMAs) were evaluated for 218 cases in the Canadian COEUR study. Non-spatial relationships between CAIX and CD8 were investigated using Spearman rank correlation, negative binomial regression and gene set enrichment analysis. Spatial relationships at the cell level were investigated using the cross K-function. Survival analysis was used to assess the relationship of CAIX and CD8 with patient survival for 154 cases. CD8 + T cell infiltration positively predicted survival with estimated hazard ratio 0.974 (95% CI 0.950, 1000). The negative binomial regression analysis found a strong TMA effect (p-value < 0.0001). It also indicated a negative association between CD8 and CAIX overall (p-value = 0.0171) and in stroma (p-value = 0.0050) but not in tumor (p-value = 0.173). Examination of the spatial association between the locations of CD8 + T cells and CAIX cells found a significant amount of heterogeneity in the first TMA, while in the second TMA there was a clear signal indicating negative spatial association in stromal regions. These results suggest that hypoxia may contribute to immune exclusion, primarily mediated by effects in stroma.

Background: The FLAURA trial demonstrated improved overall survival (OS) with first-line osimertinib for patients with epidermal growth factor receptor (EGFR) mutated advanced non-small cell lung cancer (NSCLC). We studied the efficacy and safety of osimertinib in a cohort treated during the coronavirus disease (COVID-19) pandemic.Methods: Patients diagnosed with EGFR mutated advanced NSCLC between 11 March 2020 to 31 December 2021 who received first-line osimertinib in British Columbia, Canada were identified retrospectively. Kaplan-Meier curves of OS and progression-free survival (PFS) from the start of osimertinib were plotted. The associations of baseline characteristics with PFS, and development of pneumonitis or dose reductions due to toxicity with OS were evaluated with hazard ratios estimated using univariable and multivariable Cox models.Results: The cohort comprised 231 individuals. 58.7% of patients with de novo advanced NSCLC were initially diagnosed after presentation to the Emergency Room. At osimertinib initiation, 31.6% were aged >_75 years and 45.5% had an Eastern Cooperative Oncology Group performance status (ECOG PS) >_2. Median PFS and OS were 18.0 months [95% confidence interval (CI): 16.1-26.2] and 25.4 months (95% CI: 20.3-not reached), respectively. On multivariable analysis, age >_75 years (vs. <75), ECOG PS 2/3 (vs. 0/1), ECOG PS 4 (vs. 0/1), current smokers (vs. never smokers), PD-L1 expression >_50% (vs. <1%), and L858R mutation (vs. exon 19 deletion) were associated with shorter PFS. Among 110 patients who progressed, 33.6% received subsequent therapy. 16.5% of the cohort developed grade >_3 adverse events. Pneumonitis from osimertinib (3.9% incidence) was weakly associated with shorter OS (hazard ratio: 2.59, 95% CI: 0.94-7.12, P=0.066); dose reductions were not associated with worse OS. 10.8% of patients developed COVID-19.Conclusions: In a cohort receiving first-line osimertinib during the COVID-19 pandemic, ECOG PS >_2 was observed in nearly half of patients at treatment initiation contributing to a median OS shorter than in FLAURA. The incidence of severe adverse events was low and dose reduction for drug toxicity did not impact OS. Identifying and reducing barriers to the diagnosis of NSCLC during the COVID-19 pandemic are required.

The vast coastline provides Canada with a flourishing seafood industry including bivalve shellfish production. To sustain a healthy bivalve molluscan shellfish production, the Canadian Shellfish Sanitation Program was established to monitor the health of shellfish harvesting habitats, and fecal coliform bacteria data have been collected at nearly 15,000 marine sample sites across six coastal provinces in Canada since 1979. We applied Functional Principal Component Analysis and subsequent correlation analyses to find annual variation patterns of bacteria levels at sites in each province. The overall magnitude and the seasonality of fecal contamination were modelled by functional principal component one and two, respectively. The amplitude was related to human and warm-blooded animal activities; the seasonality was strongly correlated with river discharge driven by precipitation and snow melt in British Columbia, but such correlation in provinces along the Atlantic coast could not be properly evaluated due to lack of data during winter.

The COVID-19 pandemic changed diagnostic and treatment pathways in oncology. We compared the safety and efficacy of pembrolizumab amongst advanced nonsmall cell lung cancer (NSCLC) patients with a PD-L1 tumor proportion score (TPS) ≥ 50

The Cox proportional hazards model has been pervasively used in many social science areas to examine the effects of covariates on timing to an event. The standard Cox model is intended to study univariate survival data where there is a singular event of interest, which can only be experienced once. However, we may additionally wish to explore a number of other complexities that are prevalent in survival data. For example, an individual may experience events of the same type more than once or may experience multiple types of events. This study introduces innovations in recurrent (repeatable) event analysis, jointly modeling several endogenous survival processes. As an example and an application, we simultaneously model two types of recurrent events in the presence of a dependent terminal event. This model not only correctly handles different types of recurrent events but also explicitly estimates the direction and magnitude of relationships between recurrences and survival. This article concludes with an example of the model to examine how the timing of retirement is associated with the risks of multiple spells of employment and childbearing. The theoretical discussions and empirical analyses suggest that the multivariate joint models have much to offer to a wide variety of substantive research areas.

Thyroid hormones (THs) are important developmental regulators in vertebrates, including during the metamorphosis of a tadpole into a frog. Metamorphosis is a post-embryonic developmental period initiated by TH production in the tadpole thyroid gland. The two main bioactive forms of TH are L-thyroxine (T4) and 3,5,3'-triiodothyronine (T3); these hormones have overlapping but distinct mechanisms of action. Premetamorphic tadpoles are highly responsive to TH and can be induced to metamorphose through exogenous TH exposure, making them an important model for both the study of vertebrate TH signaling and endocrine disrupting chemicals (EDCs). It is important to differentiate TH-mediated responses from estrogenic responses in premetamorphic tadpoles when assessing dysregulation by EDCs as crosstalk between the two endocrine systems is well-documented. Herein, we compare the RNA-sequencing-derived transcriptomic profiles of three TH-responsive tissues (liver, olfactory epithelium, and tail fin) in premetamorphic bullfrog (Rana [Lithobates] catesbeiana) tadpoles exposed to T3, T4, and estradiol (E2). These profiles were generated using the latest available genome assembly for the species. The data indicate that there is a clear distinction, and little overlap, between the transcriptomic responses elicited by E2 and the THs. In contrast, within the THs, the T3- and T4-induced transcriptomic profiles generally show considerable overlap; however, the degree of overlap is highly tissue-dependent, illustrating the importance of distinguishing the two THs and the affected signaling pathways within the target tissue type when evaluating hormone active agents. The data herein also show that E2 and TH treatment can uniquely induce significant changes in expression of their respective "classic" bioindicator transcripts vtg (E2) and thra, thrb, and thibz (THs). However, care must be taken in the interpretation of increased vep or esr1 transcripts as a change in transcript levels can be induced by THs rather than solely E2.

A current challenge for environmental DNA (eDNA) applications is how to account for an environmental (or false-positive) background in surveys. We performed two controlled experiments in the Goldstream Hatchery in British Columbia using a validated coho salmon (Oncorhynchus kisutch) eDNA assay (eONKI4). In the density experiment at high copy number, eDNA in 2 L water samples was measured from four 10 kL tanks containing 1 to 65 juvenile coho salmon. At these densities, we obtained a strong positive 1:1 relationship between predicted copy number/L and coho salmon biomass (g/L). The dilution experiment simulated a situation where fish leave a pool environment, and water from upstream continues to flow through at rates of 141–159 L/min. Here, three coho salmon were placed in four 10 kL tanks, removed after nine days, and the amount of remaining eDNA was measured at times coinciding with dilutions of 20, 40, 80, 160, and 1000 kL. The dilution experiment demonstrates a novel method using Binomial–Poisson distributions to detect target species eDNA at low copy number in the presence of an environmental background. This includes determination of the limit of blank with background (LOB-B) with a controlled false positive rate, and limit of detection with background (LOD-B) with a controlled false negative rate, which provides a statistically robust “Detect” or “No Detect” assessment for eDNA surveys.

Background: Programmed cell-death 1 antibodies (PD-1 Ab) improve overall survival (OS) for patients with advanced melanoma in trials; however, safety data in patients >_75 years are lacking. The prognostic significance of and risk factors for PD-1 Ab discontinuation due immune related adverse events (irAE) are also uncertain. Methods: Patients with advanced melanoma receiving frontline PD-1 Ab at British Columbia Cancer outside of clinical trials between 10/2015-10/2019 were retrospectively analyzed. The incidence and subtypes of irAE were compared between age subgroups <75 and >_ 75 years. Univariable logistic regression identified variables associated with treatment discontinuation within four months of PD-1 Ab initiation. Cox proportional hazard regression models were used to determine factors significantly associated with OS. Results: 302 patients were identified, of whom 126 (41.7%) were >_ 75 years. During all follow-up, 15.9% of patients experienced irAE grade 3/4 and 27.2% of the cohort stopped PD-1 Ab due to immune toxicity. irAE incidence, hospitalization, and need for steroids by the four-month landmark were similar amongst age groups. Advanced age was not associated with risk of PD-1 Ab discontinuation from irAE on logistic regression. For the entire cohort, pre-treatment factors associated with shorter OS on multivariable analysis were ECOG performance status >_1, M1d stage, lactate dehydrogenase >224, and neutrophil/ lymphocyte ratio >_ 5. On four-month landmark multivariable analysis, treatment discontinuation due to irAE was significantly associated with worse OS. Conclusion: Patients aged >_75 years experienced similar irAE rates and treatment discontinuation for immune toxicity compared to younger patients. As PD-1 Ab discontinuation due to irAE was associated with shorter OS, efforts to treat irAE early are warranted to potentially avoid therapy cessation. (c) 2021 Elsevier Ltd. All rights reserved.

Background The anti-programmed cell death one antibodies (Anti-PD-1 Ab) pembrolizumab or nivolumab are commonly prescribed to patients with advanced melanoma. The purpose of the current study is to identify baseline clinical characteristics associated with time to treatment initiation (TTI) of pembrolizumab or nivolumab for advanced melanoma and whether treatment delays are associated with differences in survival outcomes. Methods All patients receiving Anti-PD-1 Ab as a first-line treatment for advanced melanoma outside of clinical trials at British Columbia Cancer Agency between 10/2015 and 10/2019 were identified retrospectively. TTI was defined as the interval from pathologic diagnosis of advanced melanoma to first Anti-PD-1 Ab treatment. To determine the association between TTI and baseline characteristics, multivariable Cox proportional hazard regression analyses provided an estimate of the instantaneous relative risk of starting treatment at any time point (hazard ratio [HR] >1 indicates shorter TTI). To describe changes in overall survival (OS) observed for each four-week delay in treatment initiation, multivariable cox proportional hazard regression modelling was also performed. Results In a cohort of 302 patients, the median TTI was 52 days (interquartile range 30.2-99.0). Pulmonary metastases (M1b)/non-central nervous system visceral metastases (M1c) vs. metastases to skin or non-regional lymph nodes (M1a)(HR=1.50, 95% CI=1.12-2.02; p=0.007) and pre-treatment Eastern Cooperative Oncology Group Performance Status (ECOG PS) >1 (vs 0/1, HR=1.50, 95% CI= 1.11-2.01; p=0.008) were associated with earlier TTI. An association between treatment delay and improved OS was observed. Conclusion Patients having visceral metastases and poor baseline ECOG PS were more likely to initiate Anti-PD-1 Ab sooner. The association of shorter TTI with worse OS likely represents confounding by indication (urgent treatment offered to patients with aggressive disease).

Background: We investigated the association of peripheral blood inflammatory markers with overall survival (OS) in pembrolizumab treated advanced non-small cell lung cancer (aNSCLC) patients with programmed death ligand 1 (PD-L1) expression >= 50%. Clinical risk factors for development of immune-related adverse events (irAE) were also explored. Methods: aNSCLC patients with high PD-L1 expression receiving pembrolizumab monotherapy outside of clinical trials were identified retrospectively. All patients were treated at one of six British Columbia Cancer clinics between August 2017 and June 2019. Patients were dichotomized using baseline neutrophil-to-lymphocyte ratio (NLR, >= 6.4) and platelet-to-lymphocyte ratio (PLR, >= 441.8). Factors associated with OS were assessed with Cox proportional hazard models. Logistic regression models were utilized in landmark analysis of risk factors for irAE. Results: Among 220 patients, median age was 70.0 years, 55.0% were female, 40.5% had baseline Eastern Cooperative Oncology Group performance status (ECOG PS) 2/3, and 95.5% received frontline pembrolizumab. Median OS for the cohort was 11.8 months (95% CI: 8.7-15.4). On multivariable analysis, baseline NLR >= 6.4 [hazard ratio (HR): 2.31, 95% confidence interval (CI): 1.46-3.64, P<0.001], baseline PLR >= 441.8 (HR: 2.03, 95% CI 1.22-3.37, P=0.006), and pre-treatment ECOG PS 2/3 (HR: 2.19, 95% CI: 1.48-3.26, P<0.001) were associated with worse OS. The incidence of any grade irAE and irAE grade >= 3 were 40.5% and 12.3%, respectively. ECOG PS 2/3 (vs. 0/1) patients were at 3.76-fold higher risk of developing an irAE by the 8-month landmark (P=0.002). Conclusions: High NLR and PLR were associated with shorter OS in a cohort of patients receiving largely frontline pembrolizumab for aNSCLC in routine practice. ECOG PS 2/3 was associated with higher risk of developing an irAE. Given that NLR and PLR values are easily obtainable, prospective studies are warranted to confirm their prognostic significance in this patient population and explore a predictive utility.

AimsInduction ipilimumab and nivolumab followed by maintenance nivolumab improve overall survival compared with ipilimumab alone in patients with advanced melanoma, but immune-related adverse events (irAE) occur commonly. The need for induction discontinuation because of irAE and the relationship between irAE and survival in non-trials patients are unclear.Materials and methodsPatients with unresectable stage III–IV melanoma receiving first-line combination immunotherapy at one of six centres between December 2017 and February 2020 outside of trials were identified retrospectively. Landmark 12-week Kaplan–Meier analyses and log-rank tests were used to evaluate associations between discontinuation of induction therapy on overall survival and time to treatment failure (TTF). Multivariable analysis of factors influencing overall survival and TTF was undertaken.ResultsAmong 95 patients, the median age was 62 years, 38.9% had Eastern Cooperative Oncology Group performance status ≥1 and 22.1% had brain metastases. The median follow-up for the whole cohort was 19.8 months by the reverse Kaplan–Meier method. Any grade and grade 3–4 irAE were noted in 78.9% and 44.2% of the cohort, respectively. 44.2% of patients completed induction immunotherapy, whereas 41.1% did not due to irAE. Twelve-week landmark overall survival and TTF were similar in patients who completed induction versus those who did not due to irAE. On multivariable analysis, any grade irAE (versus none) was associated with longer overall survival (hazard ratio = 0.35, 95% confidence interval 0.15–0.82, P = 0.02) and TTF (hazard ratio = 0.38, 95% confidence interval = 0.17–0.81, P = 0.01). Grade 3–4 irAE correlated with longer TTF (hazard ratio = 0.45, 95% confidence interval = 0.20–1.01, P = 0.05).ConclusionIn this population-based cohort, discontinuation of induction immunotherapy as a result of irAE did not adversely affect overall survival or TTF. irAE observed during ipilimumab and nivolumab induction were associated with improved survival outcomes.

BACKGROUND:Patient-specific active fluid-structure interactions (FSI) model is a useful approach to non-invasively investigate the hemodynamics in the heart. However, it takes a lot of effort to obtain the proper external force boundary conditions for active models, which heavily restrained the time-sensitive clinical applications of active computational models.METHODS:The simulation results of 12 passive FSI models based on 6 patients' pre-operative and post-operative CT images were compared with corresponding active models to investigate the differences in hemodynamics and cardiac mechanics between these models.RESULTS:In comparing the passive and active models, it was found that there was no significant difference in pressure difference and shear stress on mitral valve leaflet (MVL) at the pre-SAM time point, but a significant difference was found in wall stress on the inner boundary of left ventricle (endocardium). It was also found that pressure difference on the coapted MVL and the shear stress on MVL were significantly decreased after successful surgery in both active and passive models.CONCLUSION:Our results suggested that the passive models may provide good approximated hemodynamic results at 5% RR interval, which is crucial for analyzing the initiation of systolic anterior motion (SAM). Comparing to active models, the passive models decrease the complexity of the modeling construction and the difficulty of convergence significantly. These findings suggest that, with proper boundary conditions and sufficient clinical data, the passive computational model may be a good substitution model for the active model to perform hemodynamic analysis of the initiation of SAM.

AbstractEnvironmental DNA (eDNA) has been increasingly utilized by academic, industry, and government groups for environmental monitoring due to its efficiency in regards to both time and cost, as well as non‐invasiveness to target organisms, and reduced dependency on trained biologists for sample collection. The methods typically employ quantitative real‐time polymerase chain reaction (qPCR) to detect the presence of a given organism's DNA in a sample. Currently, there is a drive to use qPCR data to infer biomass or abundance by quantitating the copy number or concentration of a given target gene fragment in a sample, which is often very dilute. Before eDNA can be fully accepted as an environmental decision‐making tool, however, certain aspects of the methods require standardization, including the quantification of target DNA in low copy number samples. Models that are not able to properly make use of data from highly dilute samples are severely hampered in their definitions of the limits of detection and quantification at the lower end of the detection curve. We propose a statistical model for a standard curve that relates the number of qPCR‐detected technical replicates to the copy number in the case of low copy number samples. Likelihood methods are used to estimate the parameters of the model and we derive inverse regression estimates together with their standard errors. Limits of copy number detection and quantification, and their confidence intervals are derived using a well‐accepted statistical approach thus providing a more broadly applicable and robust method for reporting eDNA abundance into the low copy number range. The method is illustrated using experimental results from multiple laboratories.