Standard models for a set of contingency tables with ordered response categories assume a common effect within or between tables, described by a certain type of odds ratio. In practice, heterogeneity ...usually occurs among such odds ratios, even if its extent is minor in magnitude. This article presents models that summarize the effect while simultaneously describing the degree of heterogeneity. For cases in which the levels of the stratification factor are a sample, such as many multi-center clinical trials, we recommend the use of random effects models. These treat the true stratum-specific ordinal log odds ratios as a sample with some unknown mean and standard deviation. For the random effects distribution, we consider both normality and a nonparametric approach. In using these more realistic models permitting heterogeneity, it can be more difficult to establish significance of effects because of the extra variability inherent in the model. The primary focus is three-way contingency tables with an ordinal response and a stratification factor, but we also briefly discuss models for describing heterogeneity within contingency tables.
To evaluate, in vivo, the efficacy of fine-needle capillary (nonaspiration) biopsy (FNCB) versus fine-needle aspiration biopsy (FNAB) when performed at the same site with a coaxial technique.
In 91 ...patients, biopsy was performed at 140 sites in 93 lesions mostly throughout the chest and abdomen with either FNCB or FNAB, or both (98 sites). A coaxial technique with a 22-gauge needle was used. The quality of the specimen was graded by a blinded pathologist, who also made a pathologic diagnosis.
No statistically significant difference was noted in the graded criteria performance plus diagnostic yield between the two techniques. When performed before FNAB, FNCB yielded a better quality specimen of a particular site. However, there was no difference in the graded quality of FNAB whether performed before or after FNCB. Insufficient specimens were obtained at 30 (21.4%) of 140 sites with FNCB versus only 18 (12.8%) with FNAB.
FNCB is an alternative to FNAB and provides a cellular diagnostic specimen from most lesions. When a coaxial method is used and both techniques are employed, the diagnostic accuracy of these techniques is 84%.
We compare population‐averaged and cluster‐specific models for clustered ordinal data. We consider generalized estimating equations and constrained equations maximum likelihood estimation of ...population‐averaged cumulative logit regression models, and mixed effects estimation of cluster‐specific cumulative logit regression models. A previously reported relationship between population‐averaged and cluster‐specific parameters for the binary logistic link appears to hold for analogous parameters under the cumulative logit link. We address these issues in the context of data from two cross‐over clinical trials.
Models for nominal and ordinal response data are important in many areas of research. In medical studies, patients are often evaluated on an ordinal or graded scale. Nominal data, such as types of ...services used at a hospital, are frequent in the field of health care. It is often the case that such data are nested within clusters or repeatedly assessed over time. In this dissertation we propose random effects models for analyzing longitudinal or clustered nominal and ordinal response data. Specifically, we present a general multinomial logit random effects model that we motivate within the framework of a multivariate generalized linear mixed model. As special cases of the proposed model, we consider models based on the cumulative logit, adjacent-category logit, and continuation-ratio logit link functions for analyzing ordinal response data, and the baseline-category logit link function for nominal data. For the proposed multinomial random effects models, we consider both parametric and nonparametric assumptions for the distribution of the random effects. In the parametric approach, we assume that the random effects follow a multivariate normal distribution. We consider direct maximization of the marginal likelihood using adaptive Gauss-Hermite quadrature, as well as indirect maximization using an automated Monte Carlo expectation-maximization (EM) algorithm. In addition, we propose a pseudo-likelihood approach for obtaining approximate maximum likelihood estimates. In the nonparametric approach, we assume that the random effects follow an unspecified discrete distribution. We propose an EM algorithm for obtaining nonparametric maximum likelihood estimates of the model parameters and the discrete distribution. Using simulation, we compare the performance of the parametric and nonparametric approaches when the random effects distribution is misspecified. We also examine the use of the proposed models for modeling ordinal multi-center clinical trial data. We consider random effects models that allow for a common association across all centers, as well as heterogeneous associations. We also propose Laplace and adaptive Gauss-Hermite quadrature approximated score tests for testing that a common association parameter holds in the heterogeneous random effects model. We show that the latter test performs poorly for small to moderate numbers of centers.
Compare the success of three coaxial fine-needle biopsy techniques in obtaining multiple cytologic specimens of high quality.
For each of three different biopsy needle and technique combinations ...(aspiration: 22-gauge Chiba; capillary: 22-gauge Chiba; 22-gauge Autovac aspiration biopsy gun), 30 sites (15 liver, 15 kidney) were selected for coaxial fine-needle biopsy in cadaveric liver and kidneys. For each coaxial technique, three sequential biopsies were performed through an 18-gauge coaxial needle at each of multiple sites. The quality of the resultant 270 specimens was graded by a blinded cytopathologist using a previously published grading scheme.
Using the coaxial technique, there was no significant dropoff in the cytologic specimen quality among the first, second, and third biopsies at a specific site, regardless of the order of the techniques/needles used. This was true for organs, the overall data, and for the individual five grading criteria. There was, however, a significant difference among the biopsy techniques themselves. Though there was no difference in the quality of cytopathologic specimen obtained with the Autovac aspiration gun and the aspiration technique with a 22-gauge Chiba needle, both were statistically better than the nonaspiration, capillary technique utilizing a 22-gauge needle (p = 0.0001).
The use of a coaxial technique with a fine-needle, 22-gauge biopsy offers unique advantages in obtaining a nearly unlimited amount of high-quality material for cytopathologic analysis. In this study, no dropoff was found in specimen quality with subsequent biopsies.
Abstract
Aims
We investigated the relationship between clinically assessed left ventricular ejection fraction (LVEF) and survival in a large, heterogeneous clinical cohort.
Methods and results
...Physician-reported LVEF on 403 977 echocardiograms from 203 135 patients were linked to all-cause mortality using electronic health records (1998–2018) from US regional healthcare system. Cox proportional hazards regression was used for analyses while adjusting for many patient characteristics including age, sex, and relevant comorbidities. A dataset including 45 531 echocardiograms and 35 976 patients from New Zealand was used to provide independent validation of analyses. During follow-up of the US cohort, 46 258 (23%) patients who had undergone 108 578 (27%) echocardiograms died. Overall, adjusted hazard ratios (HR) for mortality showed a u-shaped relationship for LVEF with a nadir of risk at an LVEF of 60–65%, a HR of 1.71 95% confidence interval (CI) 1.64–1.77 when ≥70% and a HR of 1.73 (95% CI 1.66–1.80) at LVEF of 35–40%. Similar relationships with a nadir at 60–65% were observed in the validation dataset as well as for each age group and both sexes. The results were similar after further adjustments for conditions associated with an elevated LVEF, including mitral regurgitation, increased wall thickness, and anaemia and when restricted to patients reported to have heart failure at the time of the echocardiogram.
Conclusion
Deviation of LVEF from 60% to 65% is associated with poorer survival regardless of age, sex, or other relevant comorbidities such as heart failure. These results may herald the recognition of a new phenotype characterized by supra-normal LVEF.
Empirical data on conditions that increase risk of coronavirus disease 2019 (COVID-19) progression are needed to identify high risk individuals. We performed a comprehensive quantitative assessment ...of pre-existing clinical phenotypes associated with COVID-19-related hospitalization.
Phenome-wide association study (PheWAS) of SARS-CoV-2-positive patients from an integrated health system (Geisinger) with system-level outpatient/inpatient COVID-19 testing capacity and retrospective electronic health record (EHR) data to assess pre-COVID-19 pandemic clinical phenotypes associated with hospital admission (hospitalization).
Of 12,971 individuals tested for SARS-CoV-2 with sufficient pre-COVID-19 pandemic EHR data at Geisinger, 1604 were SARS-CoV-2 positive and 354 required hospitalization. We identified 21 clinical phenotypes in 5 disease categories meeting phenome-wide significance (P<1.60x10-4), including: six kidney phenotypes, e.g. end stage renal disease or stage 5 CKD (OR = 11.07, p = 1.96x10-8), six cardiovascular phenotypes, e.g. congestive heart failure (OR = 3.8, p = 3.24x10-5), five respiratory phenotypes, e.g. chronic airway obstruction (OR = 2.54, p = 3.71x10-5), and three metabolic phenotypes, e.g. type 2 diabetes (OR = 1.80, p = 7.51x10-5). Additional analyses defining CKD based on estimated glomerular filtration rate, confirmed high risk of hospitalization associated with pre-existing stage 4 CKD (OR 2.90, 95% CI: 1.47, 5.74), stage 5 CKD/dialysis (OR 8.83, 95% CI: 2.76, 28.27), and kidney transplant (OR 14.98, 95% CI: 2.77, 80.8) but not stage 3 CKD (OR 1.03, 95% CI: 0.71, 1.48).
This study provides quantitative estimates of the contribution of pre-existing clinical phenotypes to COVID-19 hospitalization and highlights kidney disorders as the strongest factors associated with hospitalization in an integrated US healthcare system.
Mutations in
or
cause typical autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic kidney disease. Dominantly inherited polycystic kidney and liver diseases on the ADPKD ...spectrum are also caused by mutations in at least six other genes required for protein biogenesis in the endoplasmic reticulum, the loss of which results in defective production of the
gene product, the membrane protein polycystin-1 (PC1).
We used whole-exome sequencing in a cohort of 122 patients with genetically unresolved clinical diagnosis of ADPKD or polycystic liver disease to identify a candidate gene,
, and
cell-based assays of PC1 protein maturation to functionally validate it. For further validation, we identified carriers of
loss-of-function mutations and noncarrier matched controls in a large exome-sequenced population-based cohort and evaluated the occurrence of polycystic phenotypes in both groups.
Two patients in the clinically defined cohort had rare loss-of-function variants in
, which encodes a protein required for addition of specific mannose molecules to the assembling N-glycan precursors in the endoplasmic reticulum lumen.
assays showed that inactivation of
results in impaired maturation and defective glycosylation of PC1. Seven of the eight (88%) cases selected from the population-based cohort based on
mutation carrier state who had abdominal imaging after age 50; seven (88%) had at least four kidney cysts, compared with none in matched controls without
mutations.
is a novel disease gene in the genetically heterogeneous ADPKD spectrum. This study supports the utility of phenotype characterization in genetically-defined cohorts to validate novel disease genes, and provide much-needed genotype-phenotype correlations.
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