cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.15085734
title: Insufficient classification of anaemia in general practice: a Danish register-based observational study

description: Anaemia can be a pointer of underlying severe disease, including undiagnosed malignancy. Subsequent blood tests are essential to classify the anaemia into subtypes and to facilitate targeted diagnostic investigation to ensure timely diagnosis of underlying disease. We aimed to describe and classify anaemia based on laboratory tests from patients with new-onset anaemia detected in general practice. An additional aim was to analyse associations between patient characteristics and unclassified anaemia (not classifiable according to an algorithm). Population-based cross-sectional study. Danish general practice. A total of 62,731 patients (age: 40–90 years) with new-onset anaemia were identified in Danish laboratory information systems and nationwide registries, and data were obtained for 2014–2018. We measured the proportion of patients classified into subtypes of anaemia based on blood tests requested by general practitioners within 31 days of the anaemia index date. Of the 62,731 patients with new-onset anaemia, we identified unclassified anaemia in 78.9% (95% confidence interval (CI): 77.3–80.5) of men and 65.1% (CI: 63.4–66.9) of women. The likelihood of unclassified anaemia increased with age, increasing comorbidity and decreasing severity of anaemia. The majority of patients with new-onset anaemia could not be classified through a simple algorithm due to missing blood tests, which highlights a potential missed opportunity for diagnosis. Standardised laboratory testing of patients with anaemia is warranted to ensure adequate follow-up and early detection of underlying severe disease.KEY POINTSAnaemia can be a sign of malignancy, and anaemia classification is an important step in the diagnosis of underlying disorders.The majority of patients with anaemia could not be classified according to a simple algorithm due to missing blood tests.Some patient characteristics were associated with a high risk of unclassified anaemia: high age, high comorbidity, and severe anaemia.Standardised laboratory testing in patients with anaemia is needed to inform targeted diagnostic investigation to ensure timely diagnosis. Anaemia can be a sign of malignancy, and anaemia classification is an important step in the diagnosis of underlying disorders. The majority of patients with anaemia could not be classified according to a simple algorithm due to missing blood tests. Some patient characteristics were associated with a high risk of unclassified anaemia: high age, high comorbidity, and severe anaemia. Standardised laboratory testing in patients with anaemia is needed to inform targeted diagnostic investigation to ensure timely diagnosis.
DOI: 10.6084/m9.figshare.15109371
title: Classifying and communicating risks in prediabetes according to fasting glucose and/or glycated hemoglobin: PREDAPS cohort study

description: Information about prognostic outcomes can be of great help for people with prediabetes and for physicians in the face of scientific controversy about the cutoff point for defining prediabetes. We aimed to estimate different prognostic outcomes in people with prediabetes. Prospective cohort of subjects with prediabetes according to American Diabetes Association guidelines. The probabilities of diabetes onset versus non-onset, the odds against diabetes onset, and the probability of reverting to normoglycemia according to different prediabetes categories were calculated. The odds against diabetes onset ranged from 29:1 in individuals with isolated FPG of 100–109 mg/dL to 1:1 in individuals with FPG 110–125 mg/dL plus HbA1c 6.0–6.4%. The probability of reversion to normoglycemia was 31.2% (95% CI 24.0–39.6) in those with isolated FPG 100–109 mg/dL and 6.2% (95% CI 1.4–10.0) in those with FPG 110–125 mg/dL plus HbA1c 6.0–6.4%. Of every 100 participants in the first group, 97 did not develop diabetes and 31 reverted to normoglycemia, while in the second group those figures were 52 and 6. Using odds of probabilities and absolute numbers might be useful for people with prediabetes and physicians to share decisions on potential interventions.Key pointsCommunicating knowledge on the course of the disease to make clinical decisions is not always done appropriately.Prediabetes is an example where risk communication is important because the prognosis of subjects with prediabetes is very heterogeneous.Depending on fasting plasma glucose and HbA1c levels, the odds of probabilities against diabetes onset ranged from 29: 1 to 1: 1.Depending on fasting plasma glucose and HbA1c levels, the number of subjects in 100 who revert to normoglycemia ranged from 31 to 6.Using probabilities and number absolutes on the prognosis of prediabetes may be useful for people with prediabetes and physicians to share decisions on potential interventions. Communicating knowledge on the course of the disease to make clinical decisions is not always done appropriately. Prediabetes is an example where risk communication is important because the prognosis of subjects with prediabetes is very heterogeneous. Depending on fasting plasma glucose and HbA1c levels, the odds of probabilities against diabetes onset ranged from 29: 1 to 1: 1. Depending on fasting plasma glucose and HbA1c levels, the number of subjects in 100 who revert to normoglycemia ranged from 31 to 6. Using probabilities and number absolutes on the prognosis of prediabetes may be useful for people with prediabetes and physicians to share decisions on potential interventions.
DOI: 10.6084/m9.figshare.15109371.v1
title: Classifying and communicating risks in prediabetes according to fasting glucose and/or glycated hemoglobin: PREDAPS cohort study

description: Information about prognostic outcomes can be of great help for people with prediabetes and for physicians in the face of scientific controversy about the cutoff point for defining prediabetes. We aimed to estimate different prognostic outcomes in people with prediabetes. Prospective cohort of subjects with prediabetes according to American Diabetes Association guidelines. The probabilities of diabetes onset versus non-onset, the odds against diabetes onset, and the probability of reverting to normoglycemia according to different prediabetes categories were calculated. The odds against diabetes onset ranged from 29:1 in individuals with isolated FPG of 100–109 mg/dL to 1:1 in individuals with FPG 110–125 mg/dL plus HbA1c 6.0–6.4%. The probability of reversion to normoglycemia was 31.2% (95% CI 24.0–39.6) in those with isolated FPG 100–109 mg/dL and 6.2% (95% CI 1.4–10.0) in those with FPG 110–125 mg/dL plus HbA1c 6.0–6.4%. Of every 100 participants in the first group, 97 did not develop diabetes and 31 reverted to normoglycemia, while in the second group those figures were 52 and 6. Using odds of probabilities and absolute numbers might be useful for people with prediabetes and physicians to share decisions on potential interventions.Key pointsCommunicating knowledge on the course of the disease to make clinical decisions is not always done appropriately.Prediabetes is an example where risk communication is important because the prognosis of subjects with prediabetes is very heterogeneous.Depending on fasting plasma glucose and HbA1c levels, the odds of probabilities against diabetes onset ranged from 29: 1 to 1: 1.Depending on fasting plasma glucose and HbA1c levels, the number of subjects in 100 who revert to normoglycemia ranged from 31 to 6.Using probabilities and number absolutes on the prognosis of prediabetes may be useful for people with prediabetes and physicians to share decisions on potential interventions. Communicating knowledge on the course of the disease to make clinical decisions is not always done appropriately. Prediabetes is an example where risk communication is important because the prognosis of subjects with prediabetes is very heterogeneous. Depending on fasting plasma glucose and HbA1c levels, the odds of probabilities against diabetes onset ranged from 29: 1 to 1: 1. Depending on fasting plasma glucose and HbA1c levels, the number of subjects in 100 who revert to normoglycemia ranged from 31 to 6. Using probabilities and number absolutes on the prognosis of prediabetes may be useful for people with prediabetes and physicians to share decisions on potential interventions.
DOI: 10.6084/m9.figshare.15085734.v2
title: Insufficient classification of anaemia in general practice: a Danish register-based observational study

description: Anaemia can be a pointer of underlying severe disease, including undiagnosed malignancy. Subsequent blood tests are essential to classify the anaemia into subtypes and to facilitate targeted diagnostic investigation to ensure timely diagnosis of underlying disease. We aimed to describe and classify anaemia based on laboratory tests from patients with new-onset anaemia detected in general practice. An additional aim was to analyse associations between patient characteristics and unclassified anaemia (not classifiable according to an algorithm). Population-based cross-sectional study. Danish general practice. A total of 62,731 patients (age: 40–90 years) with new-onset anaemia were identified in Danish laboratory information systems and nationwide registries, and data were obtained for 2014–2018. We measured the proportion of patients classified into subtypes of anaemia based on blood tests requested by general practitioners within 31 days of the anaemia index date. Of the 62,731 patients with new-onset anaemia, we identified unclassified anaemia in 78.9% (95% confidence interval (CI): 77.3–80.5) of men and 65.1% (CI: 63.4–66.9) of women. The likelihood of unclassified anaemia increased with age, increasing comorbidity and decreasing severity of anaemia. The majority of patients with new-onset anaemia could not be classified through a simple algorithm due to missing blood tests, which highlights a potential missed opportunity for diagnosis. Standardised laboratory testing of patients with anaemia is warranted to ensure adequate follow-up and early detection of underlying severe disease.KEY POINTSAnaemia can be a sign of malignancy, and anaemia classification is an important step in the diagnosis of underlying disorders.The majority of patients with anaemia could not be classified according to a simple algorithm due to missing blood tests.Some patient characteristics were associated with a high risk of unclassified anaemia: high age, high comorbidity, and severe anaemia.Standardised laboratory testing in patients with anaemia is needed to inform targeted diagnostic investigation to ensure timely diagnosis. Anaemia can be a sign of malignancy, and anaemia classification is an important step in the diagnosis of underlying disorders. The majority of patients with anaemia could not be classified according to a simple algorithm due to missing blood tests. Some patient characteristics were associated with a high risk of unclassified anaemia: high age, high comorbidity, and severe anaemia. Standardised laboratory testing in patients with anaemia is needed to inform targeted diagnostic investigation to ensure timely diagnosis.
DOI: 10.6084/m9.figshare.16598981
title: Revised anatomy, taxonomy and biostratigraphy of <i>Notochampsa istedana</i> Broom, 1904, a Lower Jurassic crocodyliform from the Clarens Formation (Stormberg Group), and its implications for early crocodyliform phylogeny

description: The early-branching crocodylomorph species <i>Notochampsa istedana</i> is known from a single South African specimen collected more than 100 years ago. This species is potentially important for understanding early crocodylomorph evolution, but it is of uncertain taxonomic status and its stratigraphic position is poorly constrained. Here we reinvestigate the anatomy, taxonomy, systematics and biostratigraphy of the holotype specimen, SAM-PK-4013. SAM-PK-4013 has a unique suite of features that distinguish it from the closely related taxa <i>Orthosuchus</i> and <i>Protosuchus</i>. These features include the length and shape of the dentary symphysis, the number and shape of dentary teeth, and the number of dorsal ribs with expanded intercostal ridges. <i>Notochampsa</i> is therefore a valid taxon, and our phylogenetic analysis recovers it as sister to <i>Orthosuchus</i>, in a monophyletic Notochampsidae. <i>Notochampsa</i> and <i>Orthosuchus</i> share a ventrally expanded squamosal flange and expanded intercostal ridges on the dorsal ribs. Notochampsidae is in turn sister to Protosuchidae, forming the monophyletic group Notochampsoidea. Fieldwork and stratigraphic revisions show definitively that SAM-PK-4013 is from the Clarens Formation, approximately ∼65 m above the Elliot contact, ageing <i>Notochampsa</i> to the Pliensbachian stage, a period of vertebrate body fossil scarcity. Thus, <i>Notochampsa istedana</i> is the youngest known occurrence of a crocodylomorph (and vertebrate body fossil) from the Karoo Basin of South Africa.
DOI: 10.6084/m9.figshare.16598981.v1
title: Revised anatomy, taxonomy and biostratigraphy of <i>Notochampsa istedana</i> Broom, 1904, a Lower Jurassic crocodyliform from the Clarens Formation (Stormberg Group), and its implications for early crocodyliform phylogeny

description: The early-branching crocodylomorph species <i>Notochampsa istedana</i> is known from a single South African specimen collected more than 100 years ago. This species is potentially important for understanding early crocodylomorph evolution, but it is of uncertain taxonomic status and its stratigraphic position is poorly constrained. Here we reinvestigate the anatomy, taxonomy, systematics and biostratigraphy of the holotype specimen, SAM-PK-4013. SAM-PK-4013 has a unique suite of features that distinguish it from the closely related taxa <i>Orthosuchus</i> and <i>Protosuchus</i>. These features include the length and shape of the dentary symphysis, the number and shape of dentary teeth, and the number of dorsal ribs with expanded intercostal ridges. <i>Notochampsa</i> is therefore a valid taxon, and our phylogenetic analysis recovers it as sister to <i>Orthosuchus</i>, in a monophyletic Notochampsidae. <i>Notochampsa</i> and <i>Orthosuchus</i> share a ventrally expanded squamosal flange and expanded intercostal ridges on the dorsal ribs. Notochampsidae is in turn sister to Protosuchidae, forming the monophyletic group Notochampsoidea. Fieldwork and stratigraphic revisions show definitively that SAM-PK-4013 is from the Clarens Formation, approximately ∼65 m above the Elliot contact, ageing <i>Notochampsa</i> to the Pliensbachian stage, a period of vertebrate body fossil scarcity. Thus, <i>Notochampsa istedana</i> is the youngest known occurrence of a crocodylomorph (and vertebrate body fossil) from the Karoo Basin of South Africa.
DOI: 10.6084/m9.figshare.14396239
title: Large-Scale Hypothesis Testing for Causal Mediation Effects with Applications in Genome-wide Epigenetic Studies

description: In genome-wide epigenetic studies, it is of great scientific interest to assess whether the effect of an exposure on a clinical outcome is mediated through DNA methylations. However, statistical inference for causal mediation effects is challenged by the fact that one needs to test a large number of composite null hypotheses across the whole epigenome. Two popular tests, the Wald-type Sobel’s test and the joint significant test using the traditional null distribution are underpowered and thus can miss important scientific discoveries. In this article, we show that the null distribution of Sobel’s test is not the standard normal distribution and the null distribution of the joint significant test is not uniform under the composite null of no mediation effect, especially in finite samples and under the singular point null case that the exposure has no effect on the mediator and the mediator has no effect on the outcome. Our results explain why these two tests are underpowered, and more importantly motivate us to develop a more powerful divide-aggregate composite-null test (DACT) for the composite null hypothesis of no mediation effect by leveraging epigenome-wide data. We adopted Efron’s empirical null framework for assessing statistical significance of the DACT test. We showed analytically that the proposed DACT method had improved power, and could well control Type I error rate. Our extensive simulation studies showed that, in finite samples, the DACT method properly controlled the Type I error rate and outperformed Sobel’s test and the joint significance test for detecting mediation effects. We applied the DACT method to the U.S. Department of Veterans Affairs Normative Aging Study, an ongoing prospective cohort study which included men who were aged 21 to 80 years at entry. We identified multiple DNA methylation CpG sites that might mediate the effect of smoking on lung function with effect sizes ranging from –0.18 to –0.79 and false discovery rate controlled at the level 0.05, including the CpG sites in the genes AHRR and F2RL3. Our sensitivity analysis found small residual correlations (less than 0.01) of the error terms between the outcome and mediator regressions, suggesting that our results are robust to unmeasured confounding factors. Supplementary materials for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.
DOI: 10.6084/m9.figshare.14396239.v2
title: Large-Scale Hypothesis Testing for Causal Mediation Effects with Applications in Genome-wide Epigenetic Studies

description: In genome-wide epigenetic studies, it is of great scientific interest to assess whether the effect of an exposure on a clinical outcome is mediated through DNA methylations. However, statistical inference for causal mediation effects is challenged by the fact that one needs to test a large number of composite null hypotheses across the whole epigenome. Two popular tests, the Wald-type Sobel’s test and the joint significant test using the traditional null distribution are underpowered and thus can miss important scientific discoveries. In this article, we show that the null distribution of Sobel’s test is not the standard normal distribution and the null distribution of the joint significant test is not uniform under the composite null of no mediation effect, especially in finite samples and under the singular point null case that the exposure has no effect on the mediator and the mediator has no effect on the outcome. Our results explain why these two tests are underpowered, and more importantly motivate us to develop a more powerful divide-aggregate composite-null test (DACT) for the composite null hypothesis of no mediation effect by leveraging epigenome-wide data. We adopted Efron’s empirical null framework for assessing statistical significance of the DACT test. We showed analytically that the proposed DACT method had improved power, and could well control Type I error rate. Our extensive simulation studies showed that, in finite samples, the DACT method properly controlled the Type I error rate and outperformed Sobel’s test and the joint significance test for detecting mediation effects. We applied the DACT method to the U.S. Department of Veterans Affairs Normative Aging Study, an ongoing prospective cohort study which included men who were aged 21 to 80 years at entry. We identified multiple DNA methylation CpG sites that might mediate the effect of smoking on lung function with effect sizes ranging from –0.18 to –0.79 and false discovery rate controlled at the level 0.05, including the CpG sites in the genes AHRR and F2RL3. Our sensitivity analysis found small residual correlations (less than 0.01) of the error terms between the outcome and mediator regressions, suggesting that our results are robust to unmeasured confounding factors. Supplementary materials for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.
DOI: 10.6084/m9.figshare.14396239.v1
title: Large-Scale Hypothesis Testing for Causal Mediation Effects with Applications in Genome-wide Epigenetic Studies

description: In genome-wide epigenetic studies, it is of great scientific interest to assess whether the effect of an exposure on a clinical outcome is mediated through DNA methylations. However, statistical inference for causal mediation effects is challenged by the fact that one needs to test a large number of composite null hypotheses across the whole epigenome. Two popular tests, the Wald-type Sobel’s test and the joint significant test using the traditional null distribution are underpowered and thus can miss important scientific discoveries. In this paper, we show that the null distribution of Sobel’s test is not the standard normal distribution and the null distribution of the joint significant test is not uniform under the composite null of no mediation effect, especially in finite samples and under the singular point null case that the exposure has no effect on the mediator and the mediator has no effect on the outcome. Our results explain why these two tests are underpowered, and more importantly motivate us to develop a more powerful Divide-Aggregate Composite-null Test (DACT) for the composite null hypothesis of no mediation effect by leveraging epigenome-wide data. We adopted Efron’s empirical null framework for assessing statistical significance of the DACT test. We showed analytically that the proposed DACT method had improved power, and could well control type I error rate. Our extensive simulation studies showed that, in finite samples, the DACT method properly controlled the type I error rate and outperformed Sobel’s test and the joint significance test for detecting mediation effects. We applied the DACT method to the US Department of Veterans Affairs Normative Aging Study, an ongoing prospective cohort study which included men who were aged 21 to 80 years at entry. We identified multiple DNA methylation CpG sites that might mediate the effect of smoking on lung function with effect sizes ranging from –0.18 to –0.79 and false discovery rate controlled at level 0.05, including the CpG sites in the genes AHRR and F2RL3. Our sensitivity analysis found small residual correlations (less than 0.01) of the error terms between the outcome and mediator regressions, suggesting that our results are robust to unmeasured confounding factors.
DOI: 10.6084/m9.figshare.12851289
title: Nonparametric Maximum Likelihood Methods for Binary Response Models With Random Coefficients

description: The venerable method of maximum likelihood has found numerous recent applications in <i>nonparametric</i> estimation of regression and shape constrained densities. For mixture models the nonparametric maximum likelihood estimator (NPMLE) of Kiefer and Wolfowitz plays a central role in recent developments of empirical Bayes methods. The NPMLE has also been proposed by Cosslett as an estimation method for single index linear models for binary response with random coefficients. However, computational difficulties have hindered its application. Combining recent developments in computational geometry and convex optimization, we develop a new approach to computation for such models that dramatically increases their computational tractability. Consistency of the method is established for an expanded profile likelihood formulation. The methods are evaluated in simulation experiments, compared to the deconvolution methods of Gautier and Kitamura and illustrated in an application to modal choice for journey-to-work data in the Washington DC area. Supplementary materials for this article are available online.