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BMC Medical Research Methodology May 2023There is a pressing need to improve the accuracy of rare disease clinical study endpoints. Neutral theory, first described here, can be used to assess the accuracy of...
BACKGROUND
There is a pressing need to improve the accuracy of rare disease clinical study endpoints. Neutral theory, first described here, can be used to assess the accuracy of endpoints and improve their selection in rare disease clinical studies, reducing the risk of patient misclassification.
METHODS
Neutral theory was used to assess the accuracy of rare disease clinical study endpoints and the resulting probability of false positive and false negative classifications at different disease prevalence rates. Search strings were extracted from the Orphanet Register of Rare Diseases using a proprietary algorithm to conduct a systematic review of studies published until January 2021. Overall, 11 rare diseases with one disease-specific disease severity scale (133 studies) and 12 rare diseases with more than one disease-specific disease severity scale (483 studies) were included. All indicators from clinical studies were extracted, and Neutral theory was used to calculate their match to disease-specific disease severity scales, which were used as surrogates for the disease phenotype. For those with more than one disease-severity scale, endpoints were compared with the first disease-specific disease severity scale and a composite of all later scales. A Neutrality score of > 1.50 was considered acceptable.
RESULTS
Around half the clinical studies for half the rare diseases with one disease-specific disease severity score (palmoplantar psoriasis, achalasia, systemic lupus erythematosus, systemic sclerosis and Fournier's gangrene) met the threshold for an acceptable match to the disease phenotype, one rare disease (Guillain-Barré syndrome) had one study with an acceptable match, and four diseases (Behcet's syndrome, Creutzfeldt-Jakob disease, atypical hemolytic uremic syndrome and Prader-Willi syndrome) had no studies. Clinical study endpoints in almost half the rare diseases with more than one disease-specific DSS (acromegaly, amyotrophic lateral sclerosis, cystic fibrosis, Fabry disease and juvenile rheumatoid arthritis) were a better match to the composite, while endpoints in the remaining rare diseases (Charcot Marie Tooth disease, Gaucher disease Type I, Huntington's disease, Sjogren's syndrome and Tourette syndrome) were a worse match. Misclassifications varied with increasing disease prevalence.
CONCLUSIONS
Neutral theory confirmed that disease-severity measurement needs improvement in rare disease clinical studies, especially for some diseases, and suggested that the potential for accuracy increases as the body of knowledge on a disease increases. Using Neutral theory to benchmark disease-severity measurement in rare disease clinical studies may reduce the risk of misclassification, ensuring that recruitment and treatment effect assessment optimise medicine adoption and benefit patients.
Topics: Humans; Rare Diseases; Endpoint Determination; Clinical Studies as Topic
PubMed: 37210484
DOI: 10.1186/s12874-023-01947-z -
European Journal of Medical Genetics Jan 2022Prader-Willi Syndrome (PWS) is a multi-system genetically determined neurodevelopmental disorder and the commonest cause of syndromal obesity. The development of... (Meta-Analysis)
Meta-Analysis
Prader-Willi Syndrome (PWS) is a multi-system genetically determined neurodevelopmental disorder and the commonest cause of syndromal obesity. The development of hyperphagia in early childhood is part of the phenotype arising as a result of an impaired neural response to food intake and the inability to regulate food intake in line with energy needs. Severe obesity develops if access to food is not controlled. In this review we evaluate the evidence for increased morbidity and mortality in PWS in order to establish the extent to which it is directly related to the obesity; a consequence of the eating behaviour itself independent of obesity; or associated with other characteristics of the syndrome. Medline, Cochrane, PsychINFO, CINAHL, Web of Science and Scopus databases were used to systematically identify published material on PWS and hyperphagia and syndrome-related morbidity and mortality. One hundred and ten key papers were selected. Data on 500 people with PWS indicated that the average age of death was 21 years and obesity was, as expected, a significant factor. However, the behaviour of hyperphagia itself, independent of obesity, was also important, associated with choking, gastric rupture, and/or respiratory illness. Other syndrome-related factors increased the risk for, and seriousness of, co-morbid illness or accidents. We conclude that improving life-expectancy largely depends on managing the immediate non-obesity and obesity-related consequences of the hyperphagia, through improved support. The development of new treatments that significantly reduce the drive to eat are likely to decrease morbidity and mortality improving quality of life and life expectancy.
Topics: Humans; Hyperphagia; Morbidity; Prader-Willi Syndrome
PubMed: 34748997
DOI: 10.1016/j.ejmg.2021.104379 -
BMJ Paediatrics Open May 2024
PubMed: 38719566
DOI: 10.1136/bmjpo-2019-000630corr1 -
Tijdschrift Voor Psychiatrie 2021Prader-Willi syndrome (PWS) is a genetic syndrome characterized by dysmorphic features and endocrine, cognitive and psychiatric problems. Psychiatric problems interfere...
BACKGROUND
Prader-Willi syndrome (PWS) is a genetic syndrome characterized by dysmorphic features and endocrine, cognitive and psychiatric problems. Psychiatric problems interfere with the transition from pediatric to adult care. Psychiatric expertise is needed to facilitate this transition.
AIM
To provide a literature review on the prevalence and clinical presentation of psychiatric disorders in adults with PWS.
METHOD
A systematic literature review following the PRISMA-guidelines.
RESULTS
Thirty-three articles were included. Most adults with PWS had a specific behavioral profile with disruptive, autistic and compulsive characteristics. Psychotic symptoms occured in one third of adults with PWS, mostly in patients with maternal uniparental disomy. Mood disorders were present in 10 to 20% of adults with PWS and often accompanied by psychotic features. Studies were limited and heterogeneous in samples and methods.
CONCLUSION
There is a broad spectrum of psychiatric symptoms in adults with PWS. The clinical presentation does not fully fit within the DSM categories and shows differences between genetic subgroups. Longitudinal studies assessing the psychiatric symptoms with standardized methods are needed to improve practices on diagnosing, prevention, and treatment.
Topics: Adult; Child; Humans; Longitudinal Studies; Prader-Willi Syndrome; Psychotic Disorders; Transition to Adult Care
PubMed: 34231862
DOI: No ID Found -
Journal of Assisted Reproduction and... Jun 2018To determine whether a history of conception by assisted reproductive technology (ART) is associated with occurrence of one or more imprinting disorders of either... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
To determine whether a history of conception by assisted reproductive technology (ART) is associated with occurrence of one or more imprinting disorders of either maternal or paternal origin.
METHODS
We implemented a systematic review of scholarly literature followed by comprehensive meta-analysis to quantitatively synthesize data from reports relating to use of ART to occurrence of any imprinting disorder of humans, including Beckwith-Wiedemann (BWS), Angelman (AS), Prader-Willi (PWS), and Silver-Russell (SRS) syndromes, as well as transient neonatal diabetes mellitus (TNDB) and sporadic retinoblasoma (RB).
RESULTS
The systematic review identified 13 reports presenting unique data from 23 studies that related conception following ART to occurrence of imprinting disorders. Multiple studies of four disorder were identified, for which meta-analysis yielded the following summary estimates of associations with a history of ART: AS, summary odds ratio (sOR) = 4.7 (95% confidence interval (CI) 2.6-8.5, 4 studies); BWS, sOR = 5.8 (95% CI 3.1-11.1, 8 studies); PWS, sOR = 2.2 (95% CI 1.6-3.0, 6 studies); SRS, sOR = 11.3 (95% CI 4.5-28.5, 3 studies). Only one study reported on each of TNDB and RB.
CONCLUSION
Published data reveal positive associations between history of ART conception and each of four imprinting disorders. Reasons for these associations warrant further investigation.
Topics: Chromosome Disorders; Female; Fertilization; Genomic Imprinting; Humans; Reproductive Techniques, Assisted; Risk Factors
PubMed: 29696471
DOI: 10.1007/s10815-018-1173-x -
Effectiveness of Deep Brain Stimulation in Reducing Body Mass Index and Weight: A Systematic Review.Stereotactic and Functional Neurosurgery 2022Obesity has become a major public health concern worldwide, with current behavioral, pharmacological, and surgical treatments offering varying rates of success and...
BACKGROUND
Obesity has become a major public health concern worldwide, with current behavioral, pharmacological, and surgical treatments offering varying rates of success and adverse effects. Neurosurgical approaches to treatment of refractory obesity include deep brain stimulation (DBS) on either specific hypothalamic or reward circuitry nuclei, which might contribute to weight reduction through different mechanisms. We aimed to determine the safety and clinical effect of DBS in medical refractory obesity.
SUMMARY
Adhering to PRISMA guidelines, we performed a systematic review to identify all original studies - observational and experimental - in which DBS was performed to treat refractory obesity. From database inception to April 2021, we conducted our search in PubMed, Scopus, and LILACS databases using the following MeSH terms: "Obesity" OR "Prader-Willi Syndrome" AND "Deep Brain Stimulation." The main outcomes were safety and weight loss measured with the body mass index (BMI). The Grading of Recommendations Assessment, Development, and Evaluation methods were applied to evaluate the quality of evidence. This study protocol was registered with PROSPERO ID: CRD42019132929. Seven studies involving 12 patients met the inclusion criteria; the DBS target was the nucleus accumbens in four (57.1%), the lateral hypothalamic area in two (29.6%), and the ventral hypothalamus in one (14.3%). Further, 33% of participants had obesity secondary to Prader-Willi syndrome (PWS) and 66.6% had primary obesity. The global BMI average at baseline was 46.7 (SD: 9.6, range: 32.2-59.1), and after DBS, 42.8 (SD: 8.8, range: 25-53.9), with a mean difference of 3.9; however, the delta in PWS patients was -2.3 and 10 in those with primary obesity. The incidence of moderate side effects was 33% and included manic symptoms (N = 2), electrode fracture (N = 1), and seizure (N = 1); mild complications (41.6%) included skin infection (N = 2), difficulties falling asleep (N = 1), nausea (N = 1), and anxiety (N = 1).
KEY MESSAGES
Despite available small case series and case reports reporting a benefit in the treatment of refractory obesity with DBS, this study emphasizes the need for prospective studies with longer follow-ups in order to further address the efficacy and indications.
Topics: Body Mass Index; Deep Brain Stimulation; Humans; Nucleus Accumbens; Prospective Studies; Weight Loss
PubMed: 34583359
DOI: 10.1159/000519158 -
Clinical Genetics Dec 2019Pathogenic MAGEL2 variants result in the phenotypes of Chitayat-Hall syndrome (CHS), Schaaf-Yang syndrome (SYS) and Prader-Willi syndrome (PWS). We present five patients...
Pathogenic MAGEL2 variants result in the phenotypes of Chitayat-Hall syndrome (CHS), Schaaf-Yang syndrome (SYS) and Prader-Willi syndrome (PWS). We present five patients with mutations in MAGEL2, including the first patient reported with a missense variant, adding to the limited literature. Further, we performed a systematic review of the CHS and SYS literature, assess the overlap between CHS, SYS and PWS, and analyze genotype-phenotype correlations among them. We conclude that there is neither a clinical nor etiological difference between CHS and SYS, and propose that the two syndromes simply be referred to as MAGEL2-related disorders.
Topics: Abnormalities, Multiple; Adult; Child, Preschool; Cluster Analysis; DNA Mutational Analysis; Female; Humans; Infant; Infant, Newborn; Male; Mutation; Proteins; Young Adult
PubMed: 31397880
DOI: 10.1111/cge.13620 -
Frontiers in Endocrinology 2024[This corrects the article DOI: 10.3389/fendo.2023.1168648.].
[This corrects the article DOI: 10.3389/fendo.2023.1168648.].
PubMed: 38318297
DOI: 10.3389/fendo.2024.1357219 -
PloS One 2022This systematic review aims to describe 1) the epidemiology of the diseases indicated for treatment with growth hormone (GH) in Italy; 2) the adherence to the GH...
OBJECTIVES
This systematic review aims to describe 1) the epidemiology of the diseases indicated for treatment with growth hormone (GH) in Italy; 2) the adherence to the GH treatment in Italy and factors associated with non-adherence; 3) the economic impact of GH treatment in Italy; 4) the quality of life of patients treated with GH and their caregivers in Italy.
METHODS
Systematic literature searches were performed in PubMed, Embase and Web of Science from January 2010 to March 2021. Literature selection process, data extraction and quality assessment were performed by two independent reviewers. Study protocol has been registered in PROSPERO (CRD42021240455).
RESULTS
We included 25 studies in the qualitative synthesis. The estimated prevalence of growth hormone deficiency (GHD) was 1/4,000-10,000 in the general population of children; the prevalence of Short Stature HOmeoboX Containing gene deficiency (SHOX-D) was 1/1,000-2,000 in the general population of children; the birth prevalence of Turner syndrome was 1/2,500; the birth prevalence of Prader-Willi syndrome (PWS) was 1/15,000. Treatment adherence was suboptimal, with a range of non-adherent patients of 10-30%. The main reasons for suboptimal adherence were forgetfulness, being away from home, pain/discomfort caused by the injection. Economic studies reported a total cost for a complete multi-year course of GH treatment of almost 100,000 euros. A study showed that drug wastage can amount up to 15% of consumption, and that in some Italian regions there could be a considerable over- or under-prescribing. In general, patients and caregivers considered the GH treatment acceptable. There was a general satisfaction among patients with regard to social and school life and GH treatment outcomes, while there was a certain level of intolerance to GH treatment among adolescents. Studies on PWS patients and their caregivers showed a lower quality of life compared to the general population, and that social stigma persists.
CONCLUSION
Growth failure conditions with approved GH treatment in Italy constitute a significant burden of disease in clinical, social, and economic terms. GH treatment is generally considered acceptable by patients and caregivers. The total cost of the GH treatment is considerable; there are margins for improving efficiency, by increasing adherence, reducing drug wastage and promoting prescriptive appropriateness.
Topics: Adolescent; Child; Child, Preschool; Female; Human Growth Hormone; Humans; Italy; Male; Prader-Willi Syndrome; Prevalence; Quality of Life; Treatment Adherence and Compliance; Turner Syndrome
PubMed: 35213607
DOI: 10.1371/journal.pone.0264403 -
Growth Hormone & IGF Research :... 2021We sought to obtain a better understanding of the burden of short stature using a systematic literature review.
OBJECTIVE
We sought to obtain a better understanding of the burden of short stature using a systematic literature review.
METHODS
Studies of the burden of short stature, of any cause in adults and children, were searched using Embase, MEDLINE and Cochrane databases in April 2020, capturing publications from 2008 onwards. Case series and populations with adult-onset growth hormone deficiency (GHD) were excluded.
RESULTS
Of 1684 publications identified, 41 studies (33 in children, 8 in adults) were included. All studies assessed human burden. Most study populations in children included short stature due to GHD, idiopathic short stature (ISS) and short stature after being born small for gestational age (SGA). In these populations, four studies showed that quality of life (QoL) in children with short stature was significantly worse than in children with normal stature. A significant association between QoL and short stature was observed in children with chronic kidney disease (CKD) (3 studies), achondroplasia (1 study) and transfusion-dependent β-thalassaemia (1 study), and in samples with mixed causes of short stature (3 studies). Three studies (one in GHD/ISS/SGA and two in CKD) found no significant association between short stature and QoL, and several studies did not report statistical significance. Approximately half of adult studies showed that QoL was reduced with short stature, and the other half showed no association. Two studies, one in adults with Prader-Willi syndrome and one in children with GHD, suggested a potential association between short stature and poorer cognitive outcomes. Three studies demonstrated an increased caregiver burden in parents of children with short stature.
CONCLUSIONS
Evidence suggests that, compared with those with normal stature, children and adults with short stature of any cause may experience poorer QoL. Further research could extend our understanding of the human burden in this field.
Topics: Achondroplasia; Adult; Body Height; Caregiver Burden; Child; Cost of Illness; Growth Disorders; Human Growth Hormone; Humans; Infant, Small for Gestational Age; Parents; Quality of Life; Renal Insufficiency, Chronic; beta-Thalassemia
PubMed: 33975197
DOI: 10.1016/j.ghir.2021.101392