Co‐occurring medical conditions in adults with Down syndrome: A systematic review toward the development of health care guidelines

Adults with Down syndrome (DS) represent a unique population who are in need of clinical guidelines to address their medical care. The United States Preventive Service Task Force (USPSTF) has developed criteria for prioritizing conditions of public health importance with the potential for providing screening recommendations to improve clinical care. The quality of existing evidence needed to inform clinical guidelines has not been previously reviewed. Using the National Library of Medicine (NLM) database PubMed, we first identified 18 peer reviewed articles that addressed co‐occurring medical conditions in adults with DS. Those conditions discussed in over half of the articles were prioritized for further review. Second, we performed detailed literature searches on these specific conditions. To inform the search strategy and review process a series of key questions were formulated a priori. The quality of available evidence was then graded and knowledge gaps were identified. The number of participating adults and the design of clinical studies varied by condition and were often inadequate for answering all of our key questions. We provide data on thyroid disease, cervical spine disease, hearing impairment, overweight‐obesity, sleep apnea, congenital heart disease, and osteopenia‐osteoporosis. Minimal evidence demonstrates massive gaps in our clinical knowledge that compromises clinical decision‐making and management of these medically complex individuals. The development of evidence‐based clinical guidance will require an expanded clinical knowledge‐base in order to move forward.     

Non‐pharmacological treatment of psychiatric disorders in individuals with 22q11.2 deletion syndrome; a systematic review

22q11.2 deletion syndrome (22q11.2DS) is associated with high rates of anxiety disorders, psychotic disorders, and other psychiatric conditions. In the general population, psychiatric disorders are treated with proven pharmacological and non‐pharmacological therapies, such as cognitive behavioral therapy (CBT). To begin to assess the feasibility and efficacy of non‐pharmacological therapies in 22q11.2DS, we performed a systematic search to identify literature on non‐pharmacological interventions for psychiatric disorders in individuals with 22q11.2DS. Of 1,240 individual publications up to mid‐2016 initially identified, 11 met inclusion criteria. There were five literature reviews, five publications reporting original research (two originating from a single study), and one publication not fitting either category that suggested adaptations to an intervention without providing scientific evidence. None of the original research involved direct study of the evidence‐based non‐pharmacological therapies available for psychiatric disorders. Rather, these four studies involved computer‐based or group interventions aimed at improving neuropsychological deficits that may be associated with psychiatric disorders. Although the sample sizes were relatively small (maximum 28 participants in the intervention group), these reports documented the promising feasibility of these interventions, and improvements in domains of neuropsychological functioning, including working memory, attention, and social cognition. The results of this review underline the need for research into the feasibility and efficacy of non‐pharmacological treatments of psychiatric disorders in individuals with 22q11.2DS to inform clinical care, using larger samples, and optimally, standard randomized, placebo‐controlled, clinical trials methodology.

     

Genetic feedback for psychiatric conditions: Where are we now and where are we going

Genome‐wide association studies are rapidly advancing our understanding of the genetic architecture of complex disorders, including many psychiatric conditions such as major depression, schizophrenia, and substance use disorders. One common goal of genome‐wide association studies is to use findings for enhanced clinical prediction in the future, which can aid in identifying at‐risk individuals to enable more effective prevention screening and treatment strategies. In order to achieve this goal, we first need to gain a better understanding of the issues surrounding the return of complex genetic results. In this article, we summarize the current literature on: (a) genetic literacy in the general population, (b) the public's interest in receiving genetic test results for psychiatric conditions, (c) how individuals react to and interpret their genotypic information for specific psychiatric conditions, and (d) gaps in our knowledge that will be critical to address as we move toward returning genotypic information for psychiatric conditions in both research and clinical settings. By reviewing extant studies, we aim to increase awareness of the potential benefits and consequences of returning genotypic information for psychiatric conditions.     

Early neurodevelopmental and medical profile in children with sex chromosome trisomies: Background for the prospective eXtraordinarY babies study to identify early risk factors and targets for intervention

Sex chromosome trisomies (SCT), including Klinefelter syndrome/XXY, Trisomy X, and XYY syndrome, occur in 1 of every 500 births. The past decades of research have resulted in a broadening of known associated medical comorbidities as well as advances in psychological research. This review summarizes what is known about early neurodevelopmental, behavioral, and medical manifestations in young children with SCT. We focus on recent research and unanswered questions related to the risk for neurodevelopmental disorders that commonly present in the first years of life and discuss the medical and endocrine manifestations of SCT at this young age. The increasing rate of prenatal SCT diagnoses provides the opportunity to address gaps in the existing literature in a new birth cohort, leading to development of the eXtraordinarY Babies Study. This study aims to better describe and compare the natural history of SCT conditions, identify predictors of positive and negative outcomes in SCT, evaluate developmental and autism screening measures commonly used in primary care practices for the SCT population, and build a rich data set linked to a bank of biological samples for future study. Results from this study and ongoing international research efforts will inform evidence‐based care and improve health and neurodevelopmental outcomes.     

Leveraging population‐based exome screening to impact clinical care: The evolution of variant assessment in the Geisinger MyCode research project

Exome and genome sequencing are increasingly utilized in research studies and clinical care and can provide clinically relevant information beyond the initial intent for sequencing, including medically actionable secondary findings. Despite ongoing debate about sharing this information with patients and participants, a growing number of clinical laboratories and research programs routinely report secondary findings that increase the risk for selected diseases. Recently, there has been a push to maximize the potential benefit of this practice by implementing proactive genomic screening at the population level irrespective of medical history, but the feasibility of deploying population‐scale proactive genomic screening requires scaling key elements of the genomic data evaluation process. Herein, we describe the motivation, development, and implementation of a population‐scale variant‐first screening pipeline combining bioinformatics‐based filtering with a manual review process to screen for clinically relevant findings in research exomes generated through the DiscovEHR collaboration within Geisinger's MyCode® research project. Consistent with other studies, this pipeline yields a screen‐positive detection rate between 2.1 and 2.6% (depending on inclusion of those with prior indication‐based testing) in 130,048 adult MyCode patient‐participants screened for clinically relevant findings in 60 genes. Our variant‐first pipeline affords cost and time savings by filtering out negative cases, thereby avoiding analysis of each exome one‐by‐one, as typically employed in the diagnostic setting. While research is still needed to fully appreciate the benefits of population genomic screening, MyCode provides the first demonstration of a program at scale to help shape how population genomic screening is integrated into routine clinical care.     

Asymptomatic Cryptococcemia in Resource-Limited Settings

Despite increasing availability of anti-retroviral therapy, invasive cryptococcal disease continues to be a leading cause of death among HIV-infected individuals in resource-limited settings. Screening asymptomatic HIV-infected individuals with advanced immunosuppression for serum cryptococcal antigen clearly identifies a population at high risk of cryptococcal meningitis and death. However, screening with serum cryptococcal antigen alone identifies a heterogeneous clinical population, many of whom have mild clinical symptoms, sub-clinical meningeal infection, or fungemia. Currently, there is wide variation in practice and little evidence to guide the use of anti-fungal and anti-retroviral treatment for asymptomatic cryptococcal antigenemia (ACA). Furthermore, implementing a targeted screening and treatment intervention for ACA presents numerous operational challenges for already overburdened health care systems in resource-limited settings. While such an intervention shows promise, there are critical gaps in our understanding of ACA and its implications in the outpatient setting and an urgent need for additional research in this area.     

National down syndrome patient database: Insights from the development of a multi‐center registry study

The Down Syndrome Study Group (DSSG) was founded in 2012 as a voluntary, collaborative effort with the goal of supporting evidenced‐based health care guidelines for individuals with Down syndrome (DS). Since then, 5 DS specialty clinics have collected prospective, longitudinal data on medical conditions that co‐occur with DS. Data were entered by clinical staff or trained designees into the National Down Syndrome Patient Database, which we created using REDCap software. In our pilot year, we enrolled 663 participants across the U.S., ages 36 days to 70 years, from multiple racial and ethnic backgrounds. Here we report: (i) the demographic distribution of participants enrolled, (ii) a detailed account of our database infrastructure, and (iii) lessons learned during our pilot year to assist future researchers with similar goals for other patient populations. © 2015 Wiley Periodicals, Inc.     

Depression and the older medical patient—When and how to intervene

Depression in the elderly, particularly those with chronic physical health problems, is a common, but complex problem. In this paper we review the research literature on both the epidemiology and management of depression in the older medical patient. After a general overview of depression in the elderly, we discuss some of the particular issues relevant to depression and co-morbid physical illness amongst elderly patients. Depression can be difficult to diagnose in medically unwell older adults, particularly when there is substantial overlap in symptomatology. The epidemiology and evidence base for the treatment of depression in a number of chronic health problems common in an older adults population are then discussed, specifically cardiac disease, cerebrovascular disease, cancer, chronic kidney disease, chronic obstructive pulmonary disease, and Parkinson's disease. For many of these conditions there is emerging evidence that treatments can be effective in reducing depressive symptoms. However, these potential benefits need to be balanced against the often-increased risk of adverse events or interactions with medical treatments. Although co-morbid depression is consistently associated with poorer medical outcomes, there is limited evidence that standard anti-depressive therapy has additional benefits in terms of physical health outcomes. Collaborative care models appear particularly well suited to medically unwell older adult patients, and may provide more generalised benefits across both mental and physical health measures.     

From cause to care: Can a triple approach to better population data improve the global outlook of congenital heart disease?

Congenital heart disease (CHD) is common, costly, and critical. Approximately half of all infant deaths due to congenital anomalies are associated with CHD or neural tube defects. As infant mortality improves due to better infection control and peripartum care, congenital anomalies are becoming a key driver of pediatric survival and health. Improving CHD prevention and care globally will play a significant role toward key goals such as United Nation's sustainable development goals (SDGs) of good health and well‐being (SDG 3) and reduced inequalities (SDG 10). This review addresses two questions: how can we reinterpret and reframe available data on CHD to spur action in prevention and care? How can we re‐engineer how we currently track CHD in populations to efficiently generate new data to assess successes and detect gaps in prevention and care? Answering these questions requires understanding the causal chain of disease, from cause to CHD occurrence to health outcomes. This perspective provides a logical basis for two innovations. First, develop a data‐driven message that reframes epidemiologic and clinical data in terms of incentives for action, evidence for change, and strategies for population‐wide impact. Second, through partnerships between clinical and public health systems, implement an integrated “triple surveillance,” which, in the same population, concurrently tracks the three elements of the causal chain—causes, disease occurrence, health outcomes. By streamlining activities and minimizing operational waste, such systems can have a vital role in improving prevention and care on a population level, including in many low and middle‐income countries.     

Comorbid “treatable traits” in difficult asthma: Current evidence and clinical evaluation

The care of patients with difficult‐to‐control asthma (“difficult asthma”) is challenging and costly. Despite high‐intensity asthma treatment, these patients experience poor asthma control and face the greatest risk of asthma morbidity and mortality. Poor asthma control is often driven by severe asthma biology, which has appropriately been the focus of intense research and phenotype‐driven therapies. However, it is increasingly apparent that extra‐pulmonary comorbidities also contribute substantially to poor asthma control and a heightened disease burden. These comorbidities have been proposed as “treatable traits” in chronic airways disease, adding impetus to their evaluation and management in difficult asthma. In this review, eight major asthma‐related comorbidities are discussed: rhinitis, chronic rhinosinusitis, gastroesophageal reflux, obstructive sleep apnoea, vocal cord dysfunction, obesity, dysfunctional breathing and anxiety/depression. We describe the prevalence, impact and treatment effects of these comorbidities in the difficult asthma population, emphasizing gaps in the current literature. We examine the associations between individual comorbidities and highlight the potential for comorbidity clusters to exert combined effects on asthma outcomes. We conclude by outlining a pragmatic clinical approach to assess comorbidities in difficult asthma.     

The burden of chronic disease,multimorbidity, and polypharmacy in adults with Down syndrome

Data on clinical characteristics of adults with Down syndrome (DS) are limited and the clinical phenotype of these persons is poorly described. This study aimed to describe the occurrence of chronic diseases and pattern of medication use in a population of adults with DS. Participants were 421 community dwelling adults with DS, aged 18 years or older. Individuals were assessed through a standardized clinical protocol. Multimorbidity was defined as the occurrence of two or more chronic conditions and polypharmacy as the concomitant use of five or more medications. The mean age of study participants was 38.3 ± 12.8 years and 214 (51%) were women. Three hundred and seventy‐four participants (88.8%) presented with multimorbidity. The most prevalent condition was visual impairment (72.9%), followed by thyroid disease (50.1%) and hearing impairment (26.8%). Chronic diseases were more prevalent among participants aged >40 years. The mean number of medications used was 2.09 and polypharmacy was observed in 10.5% of the study sample. Psychotropic medications were used by a mean of 0.7 individuals of the total sample. The high prevalence of multimorbidity and the common use of multiple medications contributes to a high level of clinical complexity, which appears to be similar to the degree of complexity of the older non‐trisomic population. A comprehensive and holistic approach, commonly adopted in geriatric medicine, may provide the most appropriate care to persons with DS as they grow into adulthood.     

Hypertension and medical informatics

BACKGROUND: Only about 27% of Americans with hypertension have their disease under control. Hypertension in the African-American population has a higher prevalence (32%) and is less likely to be treated or controlled compared with that in the caucasian population. Hypertension places a significant burden on patients and health care systems. Applications of medical informatics can facilitate the management of hypertension. Examples that illustrate the utility, status, and future potential of medical informatics applications in the treatment of hypertension are presented. METHODS: Relevant studies and review articles were accessed through a PubMed search of the English-language literature and for current Internet-based information for the time period of 1993-2002. Search terms included, but were not limited to, hypertension, medical informatics, medical information science, electronic medical records, Internet, and managed care. RESULTS: There is evidence that medical informatics has a favorable impact on health care issues as it relates to patients and physicians. Although the use of computers to assist in managing hypertension is in its infancy, there are examples where informatics applications have a demonstrated clinical value. CONCLUSIONS: Management of hypertension needs much improvement. The use of computers and the Internet in health care is expanding and expected to have a positive impact on the management of chronic diseases, such as hypertension.     

Pneumonia and respiratory infections in Down syndrome: A scoping review of the literature

Pneumonia and respiratory infections impact infants and children with Down syndrome; pneumonia is a leading cause of mortality in adults with Down syndrome. We aimed to review the literature to evaluate gaps and address key questions. A series of key questions were formulated a priori to inform the search strategy and review process; addressed prevalence, severity, etiology, risk factors, preventive methods, screening, and financial costs, potential benefits or harms of screening. Using the National Library of Medicine database, PubMed, detailed literature searches on pneumonia and respiratory infections in Down syndrome were performed. Previously identified review articles were also assessed. The quality of available evidence was then evaluated and knowledge gaps were identified. Forty‐two relevant original articles were identified which addressed at least one key question. Study details including research design, internal validity, external validity, and relevant results are presented. Pneumonia and respiratory infections are more prevalent and more severe in individuals with Down syndrome compared to healthy controls through literature review, yet there are gaps in the literature regarding the etiology of pneumonia, the infectious organism, risk factors for infection, and to guide options for prevention and screening. There is urgent need for additional research studies in Down syndrome, especially in the time of the current COVID‐19 pandemic.     

Practice and application of evidence-based medicine

Evidence-based medicine is an approach to clinical practice that aims to solve the patient's problems. EBM includes five steps: identifying patient's problems, searching medical literature efficiently, critically appraising the literature(evidence), applying it to patient care, and self-assessment of these steps. Since September 1999, we have practiced the EBM approach to patient care, in inpatient and outpatient settings at the department of General Medicine of Saga Medical School. We found ourselves more clearly differentiating between the EBM approach and past conventional practice. We found EBM to be more clinically useful and we have enjoyed reading medical literature because of the focus on patient's problems. To improve our use of the EBM approach, we need to study more about clinical epidemiology to evaluate and use medical literature in patient care.     

Cancer screening in adults with down syndrome,a proposal

BackgroundThe specific distribution of cancers in Down syndrome (DS) calls into question the validity of screening policies for cancer surveillance as implemented for the general population.MethodsWe performed a literature review of cancer screening opportunities for adults with DS, taking account of the tumor profile in this specific population.ResultsIn DS, solid tumors in adults are at most half as common as in the overall group of persons with intellectual disabilities, who have a frequency similar to that of the general population. In women with DS, breast cancer is rare, the frequency of colorectal cancer is poorly described, and cervical cancer is rarely reported, although sometimes observed at an advanced stage. Young men have an increased risk of testicular cancer.DiscussionWe propose that adults with DS should participate in colon cancer screening. For women with DS, breast cancer screening is not recommended, but annual clinical monitoring should be conducted, with the option to perform ultrasound or MRI examination in suspect cases. For cervical cancer, screening could be proposed to women who are sexually active beginning at age 25 years. Annual surveillance for testicular cancer via palpation by a health professional is preferable from ages 15 to 45. In case of additional genetic predisposition in a person with DS, a surveillance similar to other family members is recommended.ConclusionThe specific tumor profile in DS warrants an adapted screening program for breast, colon, cervical and testicular neoplasia.     

Genetic diagnosis of Down syndrome in an underserved community

It is a matter of course that in high‐income countries, infants born with features suggestive of Down syndrome (DS) are offered genetic testing for confirmation of a clinical diagnosis. Benefits of a definitive diagnosis include an end to the diagnostic odyssey, informed prognosis, opportunities for caregiver support, inclusion to social support networks, and more meaningful genetic counseling. The healthcare experience for families of children born with DS in low‐ and middle‐income nations is in stark contrast with such a level of care. Barriers to obtaining genetic diagnosis might include economic disparities, geographical isolation, and lack of access to health care professionals trained in genetic medicine. As part of a combined research and community outreach effort, we provided genetic testing for several patients with DS. These individuals and their families live on several resource‐limited Caribbean islands and have either limited or virtually no access to medical genetics services. Within this group were three families with recurrent DS. Karyotype established that translocation events were not involved in the DS in any of these families. This information enabled genetic counseling to help family members understand their recurrent DS. A definitive diagnosis of DS is beneficial to families in resource‐limited communities and may help to provide such families with genetic counseling, reassurance, and peace of mind.

     

Clinical validity of expanded carrier screening: Evaluating the gene‐disease relationship in more than 200 conditions

Clinical guidelines consider expanded carrier screening (ECS) to be an acceptable method of carrier screening. However, broader guideline support and payer adoption require evidence for associations between the genes on ECS panels and the conditions for which they aim to identify carriers. We applied a standardized framework for evaluation of gene‐disease association to assess the clinical validity of conditions screened by ECS panels. The Clinical Genome Resource (ClinGen) gene curation framework was used to assess genetic and experimental evidence of associations between 208 genes and conditions screened on two commercial ECS panels. Twenty‐one conditions were previously classified by ClinGen, and the remaining 187 were evaluated by curation teams at two laboratories. To ensure consistent application of the framework across the laboratories, concordance was evaluated on a subset of conditions. All 208 evaluated conditions met the evidence threshold for supporting a gene‐disease association. Furthermore, 203 of 208 (98%) achieved the strongest (“Definitive”) level of gene‐disease association. All conditions evaluated by both commercial laboratories were similarly classified. Assessment using the ClinGen standardized framework revealed strong evidence of gene‐disease association for conditions on two ECS panels. This result establishes the disease‐level clinical validity of the panels considered herein.     

Rubinstein-Taybi syndrome medical guidelines

Children and adults with Rubinstein-Taybi Syndrome have specific medical conditions that occur with greater frequency than the general population. Based on the available information from the literature and clinical experience, recommendations for specific surveillance and interventions are made to guide those clinicians caring for individuals with Rubinstein-Taybi Syndrome. This is a first attempt at medical guidelines for individuals with RTS in the United States. On-going research is needed in many areas to guide decisions in medical care and allow for refinement of these medical guidelines.     

Hepatitis E in Qatar imported by expatriate workers from Nepal: Epidemiological characteristics and clinical manifestations

Prompted by cases of acute hepatitis in expatriate workers presenting at Alkhor Hospital, Qatar, a limited prospective observational study was conducted from July 2005 to June 2006 to determine the epidemiological and clinical features of patients (predominantly Nepalese) presenting with acute hepatitis. Countrywide during that period samples from 86 Nepalese presenting at different centers were found to be anti‐HEV IgG positive and 50 of these were also positive for anti‐HEV IgM. Fifty‐eight of those Nepalese were seen and treated at Alkhor Hospital and of them 43 were confirmed as cases of acute HEV, being positive for both anti‐HEV IgM and IgG. The remaining 15 were diagnosed as probable cases of acute HEV on the basis of clinical and epidemiological similarity. It seems likely that transit in Kathmandu in reportedly unsanitary conditions was the focus of infection. In some of those examined at Alkhor, ultrasound detected a thickened gallbladder wall in 30 of 39 (76.9%) with two cases having clinical acalcular cholecystitis. Higher levels of alanine aminotransferase and aspartate aminotransferase were associated with severe disease and derangement in coagulation. On the available evidence hepatitis E was imported by expatriate workers and it is clear that medical screening of these workers pre‐ and post‐arrival must be improved to prevent further outbreaks. It is also essential that health care workers in Qatar are made aware of this ongoing problem of imported HEV and understand the variable presentation of the condition. J. Med. Virol. 81:1047–1051, 2009. © 2009 Wiley‐Liss, Inc.