scholarly journals Future Roadmaps for Precision Medicine Applied to Diabetes: Rising to the Challenge of Heterogeneity

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
P. Bowman ◽  
S. E. Flanagan ◽  
A. T. Hattersley
Keyword(s):  
Precision Medicine ◽  
Correct Diagnosis ◽  
Large Population ◽  
Population Data ◽  
Neonatal Diabetes ◽  
Monogenic Disease ◽  
Diabetes Research ◽  
Correct Treatment ◽  
Disease Heterogeneity ◽  
Molecular Features

Precision medicine, the concept that specific treatments can be targeted to groups of individuals with specific genetic, cellular, or molecular features, is a key aspect of modern healthcare, and its use is rapidly expanding. In diabetes, the application of precision medicine has been demonstrated in monogenic disease, where sulphonylureas are used to treat patients with neonatal diabetes due to mutations in ATP-dependent potassium (KATP) channel genes. However, diabetes is highly heterogeneous, both between and within polygenic and monogenic subtypes. Making the correct diagnosis and using the correct treatment from diagnosis can be challenging for clinicians, but it is crucial to prevent long-term morbidity and mortality. To facilitate precision medicine in diabetes, research is needed to develop a better understanding of disease heterogeneity and its impact on potential treatments for specific subtypes. Animal models have been used in diabetes research, but they are not translatable to humans in the majority of cases. Advances in molecular genetics and functional laboratory techniques and availability and sharing of large population data provide exciting opportunities for human studies. This review will map the key elements of future diabetes research in humans and its potential for clinical translation to promote precision medicine in all diabetes subtypes.

scholarly journals Applied genomics in MPN presentation

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 434-439
Author(s):  
Alison R. Moliterno ◽  
Hannah Kaizer
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Bone Marrow Failure ◽  
Large Population ◽  
Population Data ◽  
Primary Myelofibrosis ◽  
Data Sets ◽  
Molecular Features ◽  
Thrombosis Risk ◽  
Risk Identify ◽  
The Individual

Abstract Polycythemia vera, essential thrombocytosis (ET), and primary myelofibrosis (PMF) are grouped together as myeloproliferative neoplasms (MPNs) because of shared clinical, pathologic, and molecular features. The 2005 discovery of the driver mutation JAK2V617F, found in more than 70% of individuals with MPNs and 98% of those with PV, has transformed the diagnosis and management of MPNs. Although PV is the most common phenotype associated with JAK2V617F, roughly 60% of individuals with ET or PMF also have the mutation, and JAK2V617F is now recognized as a common lesion in clonal hematopoiesis (CH). JAK2V617F+ CH and MPN are indolent disorders that evolve over time, with transitions to different disease phases, transformation to bone marrow failure or leukemia, and high thrombosis rates. Genomic assessment has taken center stage as an important tool to define disease phenotype, disease burden, prognosis, and even thrombosis risk of MPNs. Genomics has also unveiled the causes and factors that modify the risk of acquiring and expanding CH and MPNs and points to new pathways for targeted therapies to treat and ultimately prevent them. Genomic assessment of patients with MPNs, like other cancers, enables the clinician to capitalize on large population data sets to inform the individual patient of risk, identify treatment, and improve outcomes.

scholarly journals Assessing generalizability of a new-onset type 1 diabetes Biobank

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Colette Ciresi ◽  
Kathleen Wendholt ◽  
Maureen Mullen ◽  
Carmella Evans-Molina ◽  
Linda DiMeglio
Keyword(s):  
Type 1 Diabetes ◽  
Pancreatic Beta Cell ◽  
Large Population ◽  
Urine Samples ◽  
Diabetes Research ◽  
Newly Diagnosed ◽  
Disease Heterogeneity ◽  
Beta Cell Destruction ◽  
New Onset

Background and Hypothesis:   Type 1 diabetes (T1D) is characterized by insulin deficiency due to autoimmune pancreatic beta cell destruction. The Wells Center Pediatric Diabetes Research Program is collecting blood and urine samples from children with new onset T1D admitted to Riley Hospital. These samples are being used to discover biomarkers predictive of disease heterogeneity and course. Since not every newly-diagnosed child enrolls in the Biobank, we examined if persons enrolled are similar or different from the at-large population of newly-diagnosed children to know how generalizable samples collected are from our newly-diagnosed population.  Project Methods:    Between September 2016 and May 2018, 71 newly-diagnosed children (mean age 9.6±4.3 years) and their caregivers were approached by researchers and asked to provide blood/urine samples. Thirty-four consented/assented (as required); 21 had blood and urine collected; 13 urine only. We looked for differences in age, sex, race, BMI, socioeconomic status (based on zip code), and admission bloodwork parameters between participants and non-participants.   Results:   Overall, participants were more likely to be white and have higher admission bicarbonate. Children who provided blood and urine had no other significant differences from non-participants. Children who provided urine only were more likely to be male and to have higher admission bicarbonate than non-participants. Currently, we are obtaining data to make comparisons with the general population of all patients diagnosed at Riley.   Conclusion/Potential Impact:  Our Biobank will provide samples to explore novel biomarkers to facilitate highly-targeted therapies and to screen future preventative treatments. As we continue to collect data, it will remain important to monitor and carefully consider its generalizability. 

Nickel Allergy of the Skin and Beyond

2020 ◽  
Vol 20 (7) ◽  
pp. 1003-1009
Author(s):  
Malena Gergovska ◽  
Razvigor Darlenski ◽  
Jana Kazandjieva
Keyword(s):  
Contact Dermatitis ◽  
Allergic Contact Dermatitis ◽  
Contact Allergy ◽  
Correct Diagnosis ◽  
Large Population ◽  
Modern World ◽  
Nickel Allergy ◽  
Positive Skin ◽  
Diagnostic Potential ◽  
Allergic Contact

Background: Hypersensitization to nickel is one of the most common contact allergies in the modern world and it is considered to be a major cause of contact dermatitis, especially for hand eczema. Objective: The aim of this paper is to describe many faces of the nickel allergy and to find out different diagnostic, potential strategies for treatment and prevention in hypersensitized patients. A personal clinical experience with practical clinical cases of contact dermatitis to nickel has also been presented. Methods: Electronic databases on this topic was carried out using PubMed-Medline. Results: The literature review identified many articles reporting for nickel contact allergy and pointing the metal as number one allergen in the frequency of positive skin patch test reactions in a large population worldwide. Herein, a summary of the current understanding and evidence on nickel allergy with practical approach and proposed recommendations to the dermatologist, general practitioner, and the allergist were prepared. Conclusions: The prevalence of nickel allergy represents an important socio-economical and health issue. Metal is one of the most common sensitizing agents worldwide. The morbidity due to this metal represents the allergic contact dermatitis and it is constantly growing in many countries. There are also cases of systemic allergic contact dermatitis, where they could be easily misdiagnosed as adverse drug reactions, which lead to delay of the correct diagnosis and inappropriate treatment.

scholarly journals A Retrospective Experience of Helicobacter pylori Histology in a Large Sample of Subjects in Northern Italy

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 650
Author(s):  
Davide Giuseppe Ribaldone ◽  
Carlo Zurlo ◽  
Sharmila Fagoonee ◽  
Chiara Rosso ◽  
Angelo Armandi ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Large Population ◽  
Population Data ◽  
Signet Ring Cell ◽  
Current Data ◽  
Low Grade ◽  
Gastric Cardia Adenocarcinoma ◽  
Significant Difference ◽  
H Pylori ◽  
The Impact

Updated data about the prevalence of Helicobacter pylori (H. pylori) and its correlation with histological results are scarce. The aim of our study was to provide current data on the impact of H. pylori in a third-level endoscopy service. We performed a large, retrospective study analyzing the results of all histological samples of gastroscopy from the year 2019. In total, 1512 subjects were included. The prevalence of H. pylori was 16.8%. A significant difference between the prevalence in subjects born in Italy and those from eastern Europe, south America, or Africa was found (p < 0.0001, p = 0.006, and p = 0.0006, respectively). An association was found between H. pylori and active superficial gastritis (p < 0.0001). Current H. pylori and/or a previous finding of H. pylori was related to antral atrophy (p < 0.0001). Fifteen patients had low-grade dysplasia. There were no statistically significant associations with current or past H. pylori infection. One patient presented gastric cardia adenocarcinoma with regular gastric mucosa. One patient, H. pylori positive, was diagnosed with gastric signet ring cell adenocarcinoma in a setting of diffuse atrophy, without metaplasia.. Our study provides updated, solid (biopsy diagnosis and large population) data on the prevalence of H. pylori infection in a representative region of southern Europe.

scholarly journals NEUROD1 Is Required for the Early α and β Endocrine Differentiation in the Pancreas

2021 ◽  
Vol 22 (13) ◽  
pp. 6713
Author(s):  
Romana Bohuslavova ◽  
Ondrej Smolik ◽  
Jessica Malfatti ◽  
Zuzana Berkova ◽  
Zaneta Novakova ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Cell Mass ◽  
Neonatal Diabetes ◽  
Diabetes Research ◽  
Pancreas Development ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Islet Cell ◽  
Endocrine Differentiation

Diabetes is a metabolic disease that involves the death or dysfunction of the insulin-secreting β cells in the pancreas. Consequently, most diabetes research is aimed at understanding the molecular and cellular bases of pancreatic development, islet formation, β-cell survival, and insulin secretion. Complex interactions of signaling pathways and transcription factor networks regulate the specification, growth, and differentiation of cell types in the developing pancreas. Many of the same regulators continue to modulate gene expression and cell fate of the adult pancreas. The transcription factor NEUROD1 is essential for the maturation of β cells and the expansion of the pancreatic islet cell mass. Mutations of the Neurod1 gene cause diabetes in humans and mice. However, the different aspects of the requirement of NEUROD1 for pancreas development are not fully understood. In this study, we investigated the role of NEUROD1 during the primary and secondary transitions of mouse pancreas development. We determined that the elimination of Neurod1 impairs the expression of key transcription factors for α- and β-cell differentiation, β-cell proliferation, insulin production, and islets of Langerhans formation. These findings demonstrate that the Neurod1 deletion altered the properties of α and β endocrine cells, resulting in severe neonatal diabetes, and thus, NEUROD1 is required for proper activation of the transcriptional network and differentiation of functional α and β cells.

scholarly journals Perceptions of ‘Precision’ and ‘Personalised’ Medicine in Singapore and Associated Ethical Issues

2021 ◽  
Vol 13 (2) ◽  
pp. 179-194
Author(s):  
Serene Ong ◽  
Jeffrey Ling ◽  
Angela Ballantyne ◽  
Tamra Lysaght ◽  
Vicki Xafis
Keyword(s):  
Precision Medicine ◽  
Ethical Issues ◽  
Personalised Medicine ◽  
Large Population ◽  
Data Sets ◽  
Visual Aids ◽  
Policy Makers ◽  
The Social ◽  
Genomic Analyses ◽  
Common Understanding

AbstractGovernments are investing in precision medicine (PM) with the aim of improving healthcare through the use of genomic analyses and data analytics to develop tailored treatment approaches for individual patients. The success of PM is contingent upon clear public communications that engender trust and secure the social licence to collect and share large population-wide data sets because specific consent for each data re-use is impractical. Variation in the terminology used by different programmes used to describe PM may hinder clear communication and threaten trust. Language is used to create common understanding and expectations regarding precision medicine between researchers, clinicians and the volunteers. There is a need to better understand public interpretations of PM-related terminology. This paper reports on a qualitative study involving 24 focus group participants in the multi-lingual context of Singapore. The study explored how Singaporeans interpret and understand the terms ‘precision medicine’ and ‘personalised medicine’, and which term they felt more aptly communicates the concept and goals of PM. Results suggest that participants were unable to readily link the terms with this area of medicine and initially displayed preferences for the more familiar term of ‘personalised’. The use of visual aids to convey key concepts resonated with participants, some of whom then indicated preferences for the term ‘precision’ as being a more accurate description of PM research. These aids helped to facilitate dialogue around the ethical and social value, as well as the risks, of PM. Implications for programme developers and policy makers are discussed.

Multilevel Regression and Poststratification Versus Survey Sample Weighting for Estimating Population Quantities in Large Population Health Studies

2020 ◽  
Vol 189 (7) ◽  
pp. 717-725 ◽  
Author(s):  
Marnie Downes ◽  
John B Carlin
Keyword(s):  
Population Health ◽  
Large Scale ◽  
Census Data ◽  
Large Population ◽  
Population Data ◽  
Superior Performance ◽  
Population Parameter ◽  
Multilevel Regression ◽  
Sample Weighting ◽  
Survey Weighting

Abstract Multilevel regression and poststratification (MRP) is a model-based approach for estimating a population parameter of interest, generally from large-scale surveys. It has been shown to be effective in highly selected samples, which is particularly relevant to investigators of large-scale population health and epidemiologic surveys facing increasing difficulties in recruiting representative samples of participants. We aimed to further examine the accuracy and precision of MRP in a context where census data provided reasonable proxies for true population quantities of interest. We considered 2 outcomes from the baseline wave of the Ten to Men study (Australia, 2013–2014) and obtained relevant population data from the 2011 Australian Census. MRP was found to achieve generally superior performance relative to conventional survey weighting methods for the population as a whole and for population subsets of varying sizes. MRP resulted in less variability among estimates across population subsets relative to sample weighting, and there was some evidence of small gains in precision when using MRP, particularly for smaller population subsets. These findings offer further support for MRP as a promising analytical approach for addressing participation bias in the estimation of population descriptive quantities from large-scale health surveys and cohort studies.

scholarly journals Blood Neutrophil Counts are Associated with Exacerbation Frequency and Mortality in COPD

2020 ◽  
Author(s):  
Mike Lonergan ◽  
Alison J Dicker ◽  
Megan L Crichton ◽  
Holly R Keir ◽  
Melissa K. Van Dyke ◽  
...  
Keyword(s):  
Large Population ◽  
Real Life ◽  
Population Based ◽  
Blood Eosinophil ◽  
Blood Neutrophil ◽  
Disease Heterogeneity ◽  
Disease Information ◽  
Increased Risk ◽  
Eosinophil Counts

Abstract Background Identifying patients with COPD at increased risk of poor outcomes is challenging due to disease heterogeneity. Potential biomarkers need to be readily available in real-life clinical practice. Blood eosinophil counts are widely studied but few studies have examined the prognostic value of blood neutrophil counts (BNC). Methods In a large population-based COPD registry in the East of Scotland (TARDIS: Tayside Allergic and Respiratory Disease Information System), BNC were compared to measures of disease severity and mortality over up to 15 years follow-up. Potential mechanisms of disease modification by BNC were explored in a nested microbiome substudy. Results 178120 neutrophil counts were obtained from 7220 people (mean follow up 9 years) during stable disease periods. Median BNC was 5200cells/µL (IQR 4000-7000cells/µL). Mortality rates among those 34% with elevated BNCs (defined as 6000-15000cells/µL) at the study start were 80% higher (14.0/100 person years v 7.8/100py, P<0.001) than those with BNC in the normal range (2000-6000cells/µL). People with elevated BNC were more likely to be classified as GOLD D (46% v 33% P<0.001), have more exacerbations (mean 2.3 v 1.3/year, P<0.001), and were more likely to have severe exacerbations (13% vs. 5%, P<0.001) in the following year. Eosinophil counts were much less predictive of these outcomes. In a sub-cohort (N=276), patients with elevated BNC had increased relative abundance of Proteobacteria and reduced microbiome diversity. Conclusion High BNC may provide a useful indicator of risk of exacerbations and mortality in COPD patients.

scholarly journals Explainable Transformer-Based Neural Network forthe Prediction of Survival Outcomes in Non-SmallCell Lung Cancer (NSCLC)

2021 ◽  
Author(s):  
Gustavo Arango ◽  
Elly Kipkogei ◽  
Etai Jacob ◽  
Ioannis Kagiampakis ◽  
Arijit Patra
Keyword(s):  
Immune System ◽  
Precision Medicine ◽  
Cancer Patients ◽  
Patient Survival ◽  
Response To Therapy ◽  
Survival Models ◽  
Attractive Alternative ◽  
Survival Prediction ◽  
Molecular Features ◽  
Clinical Measurements

In this paper, we introduce the Clinical Transformer - a recasting of the widely used transformer architecture as a method for precision medicine to model relations between molecular and clinical measurements, and the survival of cancer patients. Although the emergence of immunotherapy offers a new hope for cancer patients with dramatic and durable responses having been reported, only a subset of patients demonstrate benefit. Such treatments do not directly target the tumor but recruit the patient immune system to fight the disease. Therefore, the response to therapy is more complicated to understand as it is affected by the patients physical condition, immune system fitness and the tumor. As in text, where the semantics of a word is dependent on the context of the sentence it belongs to, in immuno-therapy a biomarker may have limited meaning if measured independent of other clinical or molecular features. Hence, we hypothesize that the transformer-inspired model may potentially enable effective modelling of the semantics of different biomarkers with respect to patient survival time. Herein, we demonstrate that this approach can offer an attractive alternative to the survival models utilized incurrent practices as follows: (1) We formulate an embedding strategy applied to molecular and clinical data obtained from the patients. (2) We propose a customized objective function to predict patient survival. (3) We show the applicability of our proposed method to bioinformatics and precision medicine. Applying the clinical transformer to several immuno-oncology clinical studies, we demonstrate how the clinical transformer outperforms other linear and non-linear methods used in current practice for survival prediction. We also show that when initializing the weights of a domain-specific transformer by the weights of a cross-domain transformer, we further improve the predictions. Lastly, we show how the attention mechanism successfully captures some of the known biology behind these therapies

scholarly journals MI with Non-obstructive Coronary Artery Presenting with STEMI: A Review of Incidence, Aetiology, Assessment and Treatment

2020 ◽  
Vol 15 ◽  
Author(s):  
Ying X Gue ◽  
Rahim Kanji ◽  
Sabiha Gati ◽  
Diana A Gorog
Keyword(s):  
Acute Coronary Syndrome ◽  
Coronary Artery ◽  
Correct Diagnosis ◽  
Correct Treatment ◽  
St Segment Elevation ◽  
Coronary Syndrome ◽  
Plaque Disruption ◽  
Methodical Approach ◽  
St Segment ◽  
Assessment And Treatment

MI with non-obstructive coronary artery (MINOCA) is a condition previously thought to be benign that has recently been shown to have comparable mortality to that of acute coronary syndrome with obstructive coronary disease. The heterogeneity of the underlying aetiology makes the assessment, investigation and treatment of patients with MINOCA challenging. The majority of patients with MINOCA presenting with ST-segment elevation MI generally have an underlying coronary or myocardial cause, predominantly plaque disruption or myocarditis. In order to make the correct diagnosis, in addition to the cause of the presentation, a meticulous and methodical approach is required, with targeted investigations. Stratification of patients to guide investigations that are more likely to provide the diagnosis will allow the correct treatment to be initiated promptly. In this article, the authors review the contemporary incidence, aetiology, recommended assessment and treatment of patients with MINOCA presenting with ST-segment elevation MI.

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