scholarly journals Randomized and non-randomized designs for causal inference with longitudinal data in rare disorders

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Rima Izem ◽  
Robert McCarter
Keyword(s):  
Causal Inference ◽  
Rare Diseases ◽  
Repeated Measures ◽  
Phenotypic Diversity ◽  
Case Series ◽  
The United States ◽  
Rare Disorders ◽  
Sequential Designs ◽  
Crossover Designs ◽  
Small Patient Population

AbstractIn the United States, approximately 7000 rare diseases affect 30 million patients, and only 10% of these diseases have existing therapies. Sound study design and causal inference methods are essential to demonstrate the therapeutic efficacy, safety, and effectiveness of new therapies. In the rare diseases setting, several factors challenge the use of typical parallel control designs: the small patient population size, genotypic and phenotypic diversity, and the complexity and incomplete understanding of the disorder’s progression. Repeated measures, when spaced appropriately relative to disease progression and exploited in design and analysis, can increase study power and reduce variability in treatment effect estimation. This paper reviews these longitudinal designs and draws the parallel between some new and existing randomized studies in rare diseases and their less well-known controlled observational study designs. We show that self-controlled randomized crossover and N-of-1 designs have similar considerations as the observational case series and case-crossover designs. Also, randomized sequential designs have similar considerations to longitudinal cohort studies using sequential matching or weighting to control confounding. We discuss design and analysis considerations for valid causal inference and illustrate them with examples of analyses in multiple rare disorders, including urea cycle disorder and cystic fibrosis.

Clinical Characteristics of Patients Diagnosed with Strongyloidiasis in a United States Urban Outpatient Dermatology Department: A Case Series

2017 ◽  
Vol 1 (3) ◽  
pp. 156-160
Author(s):  
Jacqueline Watchmaker ◽  
Sean Legler ◽  
Dianne De Leon ◽  
Vanessa Pascoe ◽  
Robert Stavert
Keyword(s):  
United States ◽  
Case Series ◽  
The United States ◽  
Screening Tools ◽  
Dermatology Department ◽  
Cutaneous Manifestations ◽  
Serologic Testing ◽  
Patient Reported ◽  
History Of ◽  
Endemic Areas

Background: Although considered a tropical disease, strongyloidiasis may be encountered in non-endemic regions, primarily amongst immigrants and travelers from endemic areas.  Chronic strongyloides infection may be under-detected owing to its non-specific cutaneous presentation and the low sensitivity of commonly used screening tools. Methods: 18 consecutive patients with serologic evidence of strongyloides infestation who presented to a single urban, academic dermatology clinic between September 2013 and October 2016 were retrospectively included.  Patient age, sex, country of origin, strongyloides serology titer, absolute eosinophil count, presenting cutaneous manifestations, and patient reported subjective outcome of pruritus after treatment were obtained via chart review.  Results: Of the 18 patients, all had non-specific pruritic dermatoses, 36% had documented eosinophila and none were originally from the United States. A majority reported subjective improvement in their symptoms after treatment. Conclusion:  Strongyloides infection and serologic testing should be considered in patients living in non-endemic regions presenting with pruritic dermatoses and with a history of exposure to an endemic area.Key Points:Chronic strongyloidiasis can be encountered in non-endemic areas and clinical manifestations are variableEosinophilia was not a reliable indicator of chronic infection in this case series Dermatologists should consider serologic testing for strongyloidiasis in patients with a history of exposure and unexplained pruritus

Comparison and analysis of the fda approved orphane drugs registerand the vital and essential drugs list of the Russian Federation

2020 ◽  
pp. 4-16
Author(s):  
D.S. Yurochkin ◽  
◽  
A.A. Leshkevich ◽  
Z.M. Golant ◽  
I.A. NarkevichSaint ◽  
...  
Keyword(s):  
United States ◽  
Russian Federation ◽  
Rare Diseases ◽  
Orphan Drugs ◽  
The United States ◽  
Orphan Diseases ◽  
Essential Drugs ◽  
The Russian Federation ◽  
Comparison And Analysis ◽  
The Government

The article presents the results of a comparison of the Orphan Drugs Register approved for use in the United States and the 2020 Vital and Essential Drugs List approved on October 12, 2019 by Order of the Government of the Russian Federation No. 2406-r. The comparison identified 305 international non-proprietary names relating to the main and/or auxiliary therapy for rare diseases. The analysis of the market of drugs included in the Vital and Essential Drugs List, which can be used to treat rare (orphan) diseases in Russia was conducted.

scholarly journals Laminopathies’ Treatments Systematic Review: A Contribution Towards a ‘Treatabolome’

2021 ◽  
pp. 1-21
Author(s):  
Antonio Atalaia ◽  
Rabah Ben Yaou ◽  
Karim Wahbi ◽  
Annachiara De Sandre-Giovannoli ◽  
Corinne Vigouroux ◽  
...  
Keyword(s):  
Rare Diseases ◽  
Case Reports ◽  
Phenotypic Expression ◽  
Genetic Diagnosis ◽  
Specific Treatment ◽  
Case Series ◽  
Treatment Recommendations ◽  
Scientific Data ◽  
Bibliographic Databases ◽  
Central Registry

Background: Variants in the LMNA gene, encoding lamins A/C, are responsible for a growing number of diseases, all of which complying with the definition of rare diseases. LMNA-related disorders have a varied phenotypic expression with more than 15 syndromes described, belonging to five phenotypic groups: Muscular Dystrophies, Neuropathies, Cardiomyopathies, Lipodystrophies and Progeroid Syndromes. Overlapping phenotypes are also reported. Linking gene and variants with phenotypic expression, disease mechanisms, and corresponding treatments is particularly challenging in laminopathies. Treatment recommendations are limited, and very few are variant-based. Objective: The Treatabolome initiative aims to provide a shareable dataset of existing variant-specific treatment for rare diseases within the Solve-RD EU project. As part of this project, we gathered evidence of specific treatments for laminopathies via a systematic literature review adopting the FAIR (Findable, Accessible, Interoperable, and Reusable) guidelines for scientific data production. Methods: Treatments for LMNA-related conditions were systematically collected from MEDLINE and Embase bibliographic databases and clinical trial registries (Cochrane Central Registry of Controlled Trials, clinicaltrial.gov and EudraCT). Two investigators extracted and analyzed the literature data independently. The included papers were assessed using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence. Results: From the 4783 selected articles by a systematic approach, we identified 78 papers for our final analysis that corresponded to the profile of data defined in the inclusion and exclusion criteria. These papers include 2 guidelines/consensus papers, 4 meta-analyses, 14 single-arm trials, 15 case series, 13 cohort studies, 21 case reports, 8 expert reviews and 1 expert opinion. The treatments were summarized electronically according to significant phenome-genome associations. The specificity of treatments according to the different laminopathic phenotypical presentations is variable. Conclusions: We have extracted Treatabolome-worthy treatment recommendations for patients with different forms of laminopathies based on significant phenome-genome parings. This dataset will be available on the Treatabolome website and, through interoperability, on genetic diagnosis and treatment support tools like the RD-Connect’s Genome Phenome Analysis Platform.

Combining Microfractures, Autologous Bone Graft, and Autologous Matrix-Induced Chondrogenesis for the Treatment of Juvenile Osteochondral Talar Lesions

2017 ◽  
Vol 38 (5) ◽  
pp. 485-495 ◽  
Author(s):  
Riccardo D’Ambrosi ◽  
Camilla Maccario ◽  
Chiara Ursino ◽  
Nicola Serra ◽  
Federico Giuseppe Usuelli
Keyword(s):  
Bone Graft ◽  
Repeated Measures ◽  
Osteochondral Lesion ◽  
Young Patients ◽  
Case Series ◽  
Autologous Bone Graft ◽  
Lesion Size ◽  
Level Of Evidence ◽  
Significant Difference ◽  
Autologous Bone

Background: The purpose of this study was to evaluate the clinical and radiologic outcomes of patients younger than 20 years, treated with the arthroscopic-talus autologous matrix-induced chondrogenesis (AT-AMIC) technique and autologous bone graft for osteochondral lesion of the talus (OLT). Methods: Eleven patients under 20 years (range 13.3-20.0) underwent the AT-AMIC procedure and autologous bone graft for OLTs. Patients were evaluated preoperatively (T0) and at 6 (T1), 12 (T2), and 24 (T3) months postoperatively, using the American Orthopaedic Foot & Ankle Society Ankle and Hindfoot (AOFAS) score, the visual analog scale and the SF-12 respectively in its Mental and Physical Component Scores. Radiologic assessment included computed tomographic (CT) scan, magnetic resonance imaging (MRI) and intraoperative measurement of the lesion. A multivariate statistical analysis was performed. Results: Mean lesion size measured during surgery was 1.1 cm3 ± 0.5 cm3. We found a significant difference in clinical and radiologic parameters with analysis of variance for repeated measures ( P < .001). All clinical scores significantly improved ( P < .05) from T0 to T3. Lesion area significantly reduced from 119.1 ± 29.1 mm2 preoperatively to 77.9 ± 15.8 mm2 ( P < .05) at final follow-up as assessed by CT, and from 132.2 ± 31.3 mm2 to 85.3 ± 14.5 mm2 ( P < .05) as assessed by MRI. Moreover, we noted an important correlation between intraoperative size of the lesion and body mass index (BMI) ( P = .011). Conclusions: The technique can be considered safe and effective with early good results in young patients. Moreover, we demonstrated a significant correlation between BMI and lesion size and a significant impact of OLTs on quality of life. Level of Evidence: Level IV, retrospective case series.

scholarly journals 696. Bartonella quintana Endocarditis, A Case Series

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S400-S400
Author(s):  
Thomas D Dieringer ◽  
Glen Huang ◽  
Paul R Allyn ◽  
Jeffrey Klausner
Keyword(s):  
Renal Failure ◽  
Infective Endocarditis ◽  
Los Angeles ◽  
Aortic Valve ◽  
Literature Review ◽  
Case Series ◽  
The United States ◽  
Aortic Insufficiency ◽  
Homeless Population ◽  
Bartonella Quintana

Abstract Background Homelessness has been a growing issue in the United States and worldwide. Bartonella quintana, the causative agent of “Trench fever”, is a well known illness among homeless populations in urban centers. While many cases of B. quintana are self limited, the disease can have advanced presentations including endocarditis. We present a short case series of three cases of B. quintana infective endocarditis (IE) in homeless individuals in Los Angeles and review the literature of cases of B. quintana IE in the homeless population. Methods Here we report three cases of B. quintana IE encountered in homeless individuals at the University of California, Los Angeles (UCLA) hospital system. A literature review was also conducted. PubMed was searched for published cases of human IE secondary to B. quintana in homeless individuals. Results All three patients were male with ages ranging from 39 to 57 years old with a history of homelessness and alcohol use. Presentations were subacute to chronic in nature consisting of constitutional symptoms as well as a range of symptoms corresponding with heart and renal failure. Each patient was found to have varying degrees of aortic insufficiency with either identified aortic valve vegetation or valvular thickening. Diagnosis was made with a combination of Bartonella serologies and whole genome sequencing PCR. All three patient’s courses were complicated by renal failure at varying points limiting the use of gentamicin for the full treatment course. Two patients ultimately underwent aortic valve replacement due to severe aortic insufficiency and completed therapy with doxycycline and rifampin. A single patient was discharged with plan to complete doxycycline and rifampin therapy however was lost to follow up. A literature review of 10 manuscripts describing 13 cases of B. quintana IE were identified. All the patients were male and the median age was 45. Six of the cases were in Europe and eight were in North America. All cases had left sided valve involvement (10 aortic, 6 mitral, 3 both valves). No cases of right sided IE were identified. Conclusion B. quintana IE should be considered in homeless patients with a clinical presentation concerning for IE. A combination of serology and PCR testing can be useful in diagnosis of this uncommon cause of infective endocarditis. Disclosures Jeffrey Klausner, MD, MPH, Nothing to disclose

scholarly journals Autologous Matrix-Induced Chondrogenesis for Treatment of Focal Cartilage Defects in the Knee: A Follow-up Study

2021 ◽  
Vol 9 (2) ◽  
pp. 232596712098187
Author(s):  
Justus Gille ◽  
Ellen Reiss ◽  
Moritz Freitag ◽  
Jan Schagemann ◽  
Matthias Steinwachs ◽  
...  
Keyword(s):  
Repeated Measures ◽  
Demographic Data ◽  
Case Series ◽  
Defect Size ◽  
Lysholm Score ◽  
Outcome Analysis ◽  
Cartilage Defects ◽  
Chondral Defects ◽  
The Mean

Background: Autologous matrix-induced chondrogenesis (AMIC) is a well-established treatment for full-thickness cartilage defects. Purpose: To evaluate the long-term clinical outcomes of AMIC for the treatment of chondral lesions of the knee. Study Design: Case series; Level of evidence, 4. Methods: A multisite prospective registry recorded demographic data and outcomes for patients who underwent repair of chondral defects. In total, 131 patients were included in the study. Lysholm, Knee injury and Osteoarthritis Outcome Score (KOOS), and visual analog scale (VAS) score for pain were used for outcome analysis. Across all patients, the mean ± SD age of patients was 36.6 ± 11.7 years. The mean body weight was 80.0 ± 16.8 kg, mean height was 176.3 ± 7.9 cm, and mean defect size was 3.3 ± 1.8 cm2. Defects were classified as Outerbridge grade III or IV. A repeated-measures analysis of variance was used to compare outcomes across all time points. Results: The median follow-up time for the patients in this cohort was 4.56 ± 2.92 years. Significant improvement ( P < .001) in all scores was observed at 1 to 2 years after AMIC, and improved values were noted up to 7 years postoperatively. Among all patients, the mean preoperative Lysholm score was 46.9 ± 19.6. At the 1-year follow-up, a significantly higher mean Lysholm score was noted, with maintenance of the favorable outcomes at 7-year follow-up. The KOOS also showed a significant improvement of postoperative values compared with preoperative data. The mean VAS had significantly decreased during the 7-year follow-up. Age, sex, and defect size did not have a significant effect on the outcomes. Conclusion: AMIC is an effective method of treating chondral defects of the knee and leads to reliably favorable results up to 7 years postoperatively.

scholarly journals Standing on the shoulders of Giants: a citation analysis of the paediatric congenital heart disease literature

2021 ◽  
pp. 1-9
Author(s):  
Daniel P. Sew ◽  
Nigel E. Drury
Keyword(s):  
Citation Analysis ◽  
San Francisco ◽  
Citation Count ◽  
Case Series ◽  
Scientific Progress ◽  
The United States ◽  
Original Research ◽  
Prolific Author ◽  
Journal Citation Reports ◽  
The Impact

Abstract Objective: The citation history of a published article reflects its impact on the literature over time. We conducted a comprehensive bibliometric analysis to identify the most cited papers on CHD in children. Methods: One-hundred and ninety journals listed in Journal Citation Reports were accessed via Web of Science. Publications with 250 or more citations were identified from Science Citation Index Expanded (1900–2020), and those relating to structural CHD in children were reviewed. Articles were ranked by citation count and the 100 most cited were analysed. Results: The number of citations ranged from 2522 to 309 (median 431, IQR 356–518), with 35 published since 2000. All were written in English, most originated from the United States (74%), and were published in cardiovascular journals, with Circulation (28%) the most frequent. There were 86 original research articles, including 50 case series, 14 cohort studies, and 10 clinical trials. The most cited paper was by Hoffman JI and Kaplan S on the incidence of CHD. Thirteen authors had 4 or more publications in the top 100, all of whom had worked in Boston, Philadelphia, San Francisco, or Dallas, and the most prolific author was Newburger JW (9 articles). Conclusions: Citation analysis provides a historical perspective on scientific progress by assessing the impact of individual articles. Our study highlights the dominant position of US-based researchers and journals in this field. Most of the highly cited articles remain case series, with few randomised controlled trials in CHD appearing in recent years.

scholarly journals The Use of External Controls in FDA Regulatory Decision Making

2021 ◽  
Author(s):  
Mahta Jahanshahi ◽  
Keith Gregg ◽  
Gillian Davis ◽  
Adora Ndu ◽  
Veronica Miller ◽  
...  
Keyword(s):  
Decision Making ◽  
Natural History ◽  
Product Development ◽  
Rare Diseases ◽  
The United States ◽  
External Control ◽  
Common Source ◽  
Published Data ◽  
History Data ◽  
Benefit Risk Assessment

AbstractThe regulatory standards of the United States Food and Drug Administration (FDA) require substantial evidence of effectiveness from adequate and well-controlled trials that typically use a valid comparison to an internal concurrent control. However, when it is not feasible or ethical to use an internal control, particularly in rare disease populations, relying on external controls may be acceptable. To better understand the use of external controls to support product development and approval, we reviewed FDA regulatory approval decisions between 2000 and 2019 for drug and biologic products to identify pivotal studies that leveraged external controls, with a focus on select therapeutic areas. Forty-five approvals were identified where FDA accepted external control data in their benefit/risk assessment; they did so for many reasons including the rare nature of the disease, ethical concerns regarding use of a placebo or no-treatment arm, the seriousness of the condition, and the high unmet medical need. Retrospective natural history data, including retrospective reviews of patient records, was the most common source of external control (44%). Other types of external control were baseline control (33%); published data (11%); and data from a previous clinical study (11%). To gain further insights, a comprehensive evaluation of selected approvals utilizing different types of external control is provided to highlight the variety of approaches used by sponsors and the challenges encountered in supporting product development and FDA decision making; particularly, the value and use of retrospective natural history in the development of products for rare diseases. Education on the use of external controls based on FDA regulatory precedent will allow for continued use and broader application of innovative approaches to clinical trial design, while avoiding delays in product development for rare diseases. Learnings from this review also highlight the need to update regulatory guidance to acknowledge the utility of external controls, particularly retrospective natural history data.

scholarly journals EXPERIENCE WITH USING RAPID MOLECULAR TESTING IN DIAGNOSING PULMONARY AND EXTRA-PULMONARY PEDIATRIC TUBERCULOSIS IN A NON-ENDEMIC SETTING - A RETROSPECTIVE CASE SERIES

2018 ◽  
Vol 23 (suppl_1) ◽  
pp. e44-e45 ◽  
Author(s):  
Hana Mijovic ◽  
Yossef Al-Nasser ◽  
Ghada Al-Rawahi ◽  
Ashley Roberts
Keyword(s):  
Case Series ◽  
Pericardial Fluid ◽  
Diagnosis And Treatment ◽  
Molecular Testing ◽  
Retrospective Case ◽  
Detection Rates ◽  
Endemic Setting ◽  
Number Of Patients ◽  
Small Patient Population ◽  
Extra Pulmonary

Abstract BACKGROUND Tuberculosis (TB) is a rare but potentially devastating infection among Canadian children. Accurate diagnosis and initiation of treatment are limited in part by the fact that it takes 2–6 weeks for culture results to be confirmed. Xpert MTB/RIF (Xpert) is a rapid, automated molecular assay that has been validated for diagnosing pulmonary but not extra-pulmonary TB in children. OBJECTIVES This was a retrospective study of children investigated for active TB at our facility in order to: 1.Outline demographic characteristics and describe clinical presentations of children diagnosed with active TB. 2.Compare performance of molecular testing (Xpert) to stain and Mycobacterium tuberculosis culture on pulmonary and extra-pulmonary specimens. DESIGN/METHODS We conducted a retrospective chart review of all paediatric patients investigated for active TB at our facility with stain, culture and molecular (Xpert) testing between January 2015 and August 2017. Due to a small number of patients, our data analysis was limited to narrative summary and descriptive statistics. RESULTS A total of 10 children were diagnosed with active TB, including 3 cases of pulmonary, 4 extra-pulmonary and 3 disseminated disease. Age range at diagnosis was 2 months to 16 years, with 3 children younger than 1 year. Most children contracted TB while travelling to and/or being exposed to an index case from endemic areas, including East Asia/Western Pacific (5), South Asia (2) and Africa (1). All children were HIV negative. Time from symptom onset to TB diagnosis and treatment ranged from approximately 4 days to 5 months. Multi-drug resistant TB was confirmed in 1 child. Sadly, 1 child passed away from TB related complications. AFB stain was positive on at least one specimen in 4/10 cases, cultures were positive in 8/10 and molecular testing (Xpert) in 7/10 cases. Time to positive cultures ranged from 10 to 35 days, with an average of 19 days. All cases positive on Xpert were also culture positive. Xpert test diagnosed TB in 5/6 of extra-pulmonary specimens submitted, including pericardial fluid, lymph node tissues and cerebrospinal fluid. CONCLUSION Many paediatric TB patients at our facility are children who have traveled to/have contacts from TB endemic regions, emphasizing the need for obtaining thorough exposure and travel history. Culture and molecular testing demonstrated similar TB detection rates, albeit based on a small patient population. While cultures remain the most reliable diagnostic method, molecular testing may facilitate rapid diagnosis and treatment of pulmonary and extra-pulmonary paediatric TB in a non-endemic setting.

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