Pranesh Chakraborty

The Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada

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Publications (36)108.76 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: In this article we review the literature regarding the public understanding of the potential benefits and burdens of expanded newborn bloodspot screening. We draw attention to broadened notions of benefit that go beyond early identification of asymptomatic individuals and resultant intervention to reduce morbidity or mortality, and include benefits gained by families through knowledge that may facilitate life choices, as well as gains generated by avoiding diagnostic delays. We also reflect on burdens such as increasing false-positive results and parental anxiety, together with risks of overdiagnosis when the natural history of a condition is poorly understood. We conclude that these expanded notions of benefit and burden bring with them implications for parental consent and confidentiality in the context of secondary use of residual bloodspots. Balancing benefits and burdens will be even more pertinent given technological advances that may permit whole exome or genome sequencing within newborn screening programs.
    Personalized Medicine 08/2014; · 1.51 Impact Factor
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    ABSTRACT: Accumulation of propionylcarnitine (C3) in neonatal dried blood spots (DBS) is indicative of inborn errors of propionate metabolism including propionic acidemia (PA), methylmalonic aciduria (MMA), and cobalamin (Cbl) metabolic defects. Concentrations of C3 in affected newborns overlap with healthy individuals rendering this marker neither specific nor sensitive. While a conservative C3 cutoff together with relevant acylcarnitines ratios improve screening sensitivity, existing mass spectrometric methods in newborn screening laboratories are inadequate at improving testing specificity. Therefore, using the original screening DBS, we sought to measure 2-methylcitric acid (MCA), a pathognomonic hallmark of C3 disorders to decrease the false positive rate and improve the positive predictive value of C3 disorders. MCA was derivatized with 4-[2-(N,N-dimethylamino)ethylaminosulfonyl]-7-(2-aminoethylamino)-2,1,3-benzoxadiazole (DAABD-AE). No separate extraction step was required and derivatization was performed directly using a 3.2-mm disc of DBS as a sample (65°C for 45 min). The reaction mixture was analyzed by liquid chromatography tandem mass spectrometry. MCA was well separated and eluted at 2.3 min with a total run time of 7 min. The median and (range) of MCA of 0.06 μmol/L (0-0.63) were in excellent agreement with the literature. The method was applied retrospectively on DBS samples from established patients with PA, MMA, Cbl C, Cbl F, maternal vitamin B12 deficiency (n = 20) and controls (n = 337). Comparison with results obtained by another method was satisfactory (n = 252). This method will be applied as a second tier test for samples which trigger positive PA or MMA results by the primary newborn screening method.
    JIMD reports. 07/2014;
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    ABSTRACT: Introduction: Newborn bloodspot screening is routinely offered to all newborn babies in Canada. As with many procedures for children, this requires proxy decision-making on the part of the parents. In addition, technical advances have led to a situation where the information generated by screening can exceed providers’ capacity to intervene therapeutically. Studies have indicated support for mandated screening in the case of treatable conditions, and a need for consent for those that are not treatable. However, these studies assume that parents have a shared understanding of terms such as informed or implied consent, but also the requirements that the different approaches create. To date, there has been little exploration of the perceived benefits or drawbacks from alternative consent approaches. Objective: To explore the attitudes of parents towards different consent approaches for newborn bloodspot screening. Methods: Qualitative interviews with parents in Ontario and Newfoundland & Labrador, Canada. Results & Conclusion: We will present the results of semi-structured interviews with parents regarding consent practices for newborn bloodspot screening. Specifically, we present results of thematic analyses focussing on parent interpretations of key terms such as informed consent and implied consent, together with evaluations of necessary requirements for different approaches within the newborn screening context. In particular we report perceived differences between these approaches, and practicalities required by the differing approaches to consent.
    2014 Joint Garrod and Canadian Newborn & Child Screening Symposium,, Ottawa, Ontario; 05/2014
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    ABSTRACT: Glycyl-tRNA synthetase (GARS) is an aminoacyl-tRNA synthetase (ARS) that links the amino acid glycine to its corresponding tRNA prior to protein translation and is one of three bifunctional ARS that are active within both the cytoplasm and mitochondria. Dominant mutations in GARS cause rare forms of Charcot-Marie-Tooth disease and distal spinal muscular atrophy. We report a 12-year old girl who presented with clinical and biochemical features of a systemic mitochondrial disease including exercise-induced myalgia, non-compaction cardiomyopathy, persistent elevation of blood lactate and alanine and MRI evidence of mild periventricular leukomalacia. Using exome sequencing she was found to harbor compound heterozygous mutations within the glycyl-tRNA synthetase (GARS) gene; c.1904C > T; p.Ser635Leu and c.1787G > A; p.Arg596Gln. Each mutation occurred at a highly conserved site within the anticodon binding domain. Our findings suggest that recessive mutations in GARS may cause systemic mitochondrial disease. This phenotype is distinct from patients with previously reported dominant mutations in this gene, thereby expanding the spectrum of disease associated with GARS dysregulation.
    BMC Medical Genetics 03/2014; 15(1):36. · 2.54 Impact Factor
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    ABSTRACT: Growing discussion on the use of whole-genome or exome sequencing (WG/ES) in newborn screening (NBS) has raised concerns regarding the generation of incidental information on millions of infants annually. It is unknown whether integrating WG/ES would alter public expectations regarding participation in universal NBS. We assessed public willingness to participate in NBS using WG/ES compared with current NBS. Our secondary objective was to assess the public's beliefs regarding a parental responsibility to participate in WG/ES-based NBS compared with current NBS. We examined self-reported attitudes regarding willingness to participate in NBS using a cross-sectional national survey of Canadian residents recruited through an internet panel, reflective of the Canadian population by age, gender and region. Our results showed that fewer respondents would be willing to participate in NBS using WG/ES compared with NBS using current technologies (80 vs 94%, P<0.001), or perceived a parental responsibility to participate in WG/ES-based NBS vs current NBS (30 vs 48%, P<0.001). Our findings suggest that integrating WG/ES into NBS might reduce participation, and challenge the moral authority that NBS programmes rely upon to ensure population benefits. These findings point to the need for caution in the untargeted use of WG/ES in public health contexts.European Journal of Human Genetics advance online publication, 19 February 2014; doi:10.1038/ejhg.2014.22.
    European journal of human genetics: EJHG 02/2014; · 3.56 Impact Factor
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    ABSTRACT: Background:Prematurity may influence amino acids, enzymes and endocrine markers levels obtained through newborn screening. Identifying which analytes are the most affected by degree of prematurity could provide insight into how prematurity impacts metabolism.Methods:We examined the associations between degree of prematurity and levels of amino acids, enzymes and endocrine markers in all newborns with and without adjustment for birth weight, feeding status, sample timing, transfusion and sex.Results:Our analysis included 373,819 children born at term (> 36 weeks gestation), 26,483 near-term children (33-36 weeks gestation), 4354 very premature children (28-32 weeks gestation) and 1146 extremely premature children (<28 weeks gestation). Of the amino acids showing consistent trends across categories of prematurity, the levels of 3 amino acids (arginine, leucine and valine) were at least 50% different between extremely premature and term children. Levels of 17-hydroxyprogesterone (17-OHP) increased with increasing prematurity while thyrotropin stimulating hormone (TSH) values consistently decreased with increasing prematurity. None of the three enzyme markers we examined showed a trend in levels across categories of prematurity.Conclusion:This study demonstrates that children at different stages of prematurity are metabolically distinct. Future research should focus on the mechanism by which prematurity impacts upon the specific analytes influenced by prematurity.Pediatric Research (2013); doi:10.1038/pr.2013.212.
    Pediatric Research 11/2013; · 2.67 Impact Factor
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    ABSTRACT: To examine the role of primary care providers in informing and supporting families who receive positive screening results. Cross-sectional survey. Ontario. Family physicians, pediatricians, and midwives involved in newborn care. Beliefs, practices, and barriers related to providing information to families who receive positive screening results for their newborns. A total of 819 providers participated (adjusted response rate of 60.9%). Of the respondents, 67.4% to 81.0% agreed that it was their responsibility to provide care to families of newborns who received positive screening results, and 64.2% to 84.8% agreed they should provide brochures or engage in general discussions about the identified conditions. Of the pediatricians, 67.3% endorsed having detailed discussions with families, but only 24.1% of family physicians and 27.6% of midwives endorsed this practice. All provider groups reported less involvement in information provision than they believed they should have. This discrepancy was most evident for family physicians: most stated that they should provide brochures (64.2%) or engage in general discussions (73.5%), but only a minority did so (15.3% and 27.7%, respectively). Family physicians reported insufficient time (42.2%), compensation (52.2%), and training (72.3%) to play this role, and only a minority agreed they were up to date (18.5%) or confident (16.5%) regarding newborn screening. Providers of primary newborn care see an information-provision role for themselves in caring for families who receive positive newborn screening results. Efforts to further define the scope of this role combined with efforts to mitigate existing barriers are warranted.
    Canadian family physician Medecin de famille canadien 08/2013; 59(8):861-8. · 1.19 Impact Factor
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    ABSTRACT: Methylmalonate semialdehyde dehydrogenase (MMSDH) deficiency is a rare autosomal recessive disorder with varied metabolite abnormalities, including accumulation of 3-hydroxyisobutyric, 3-hydroxypropionic, 3-aminoisobutyric and methylmalonic acids, as well as beta-alanine. Existing reports describe a highly variable clinical and biochemical phenotype, which can make diagnosis a challenge. To date, only three reported cases have been confirmed at the molecular level, through identification of homozygous mutations in ALDH6A1, the gene encoding MMSDH. Confirmation by enzyme assay has until now not been possible, due to the extreme instability of the enzyme substrate.Methods and results: We report a child with severe developmental delays, abnormal myelination on brain MRI, and transient/variable elevations in lactate, methylmalonic acid, 3-hydroxyisobutyric and 3-aminoisobutyric acids. Compound heterozygous mutations were identified by exome sequencing and confirmed by Sanger sequencing within exon 6 (c.514 T > C; p. Tyr172His) and exon 12 (c.1603C > T; p. Arg535Cys) of ALDH6A1. The resulting amino acid changes, both occurring in residues conserved among mammals, are predicted to be damaging at the protein level. Subsequent MMSDH enzyme assay demonstrated reduced activity in patient fibroblasts, measuring 2.5 standard deviations below the mean. We present the fourth reported case of MMSDH deficiency with confirmation at the molecular level, and expand on what is already an extremely variable clinical and biochemical phenotype. Furthermore, this is the first report to demonstrate a corresponding reduction in MMSDH enzyme activity. This report illustrates the emerging utilization of whole exome sequencing and variant data filtering using clinical data as an early tool in the diagnosis of rare and variable conditions.
    Orphanet Journal of Rare Diseases 07/2013; 8(1):98. · 4.32 Impact Factor
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    ABSTRACT: Key points A novel clinical syndrome of congenital sideroblastic anemia, B cell immunodeficiency, periodic fevers and developmental delay is describedBone marrow transplant resulted in complete and durable resolution of the hematologic and immunologic manifestations.
    Blood 04/2013; · 9.78 Impact Factor
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    ABSTRACT: Context:Recent studies in critically ill populations have suggested both adrenal insufficiency (AI) and vitamin D deficiency to be associated with worse clinical outcome. There are multiple mechanisms through which these pleiotropic hormones might synergistically influence critical illness.Objective:The aim of the study was to investigate potential relationships between vitamin D status, adrenal status, and cardiovascular dysfunction in critically ill children.Design:We conducted a secondary analysis of data from a prospective cohort study.Setting and Patients:The study was conducted on 319 children admitted to 6 Canadian tertiary-care pediatric intensive care units.Main Outcome Measures:Vitamin D status was determined through total 25-hydroxyvitamin D (25OHD) levels. AI was defined as a cortisol increment under 9 μg/dL after low-dose cosyntropin. Clinically significant cardiovascular dysfunction was defined as catecholamine requirement during pediatric intensive care unit admission.Results:Using 3 different thresholds to define vitamin D deficiency, no association was found between vitamin D status and AI. Furthermore, linear regression failed to identify a relationship between 25OHD and baseline or post-cosyntropin cortisol. However, the association between AI and cardiovascular dysfunction was influenced by vitamin D status; compared to children with 25OHD above 30 nmol/L, AI in the vitamin D-deficient group was associated with significantly higher odds of catecholamine use (odds ratio, 5.29 vs 1.63; P = .046).Conclusions:We did not find evidence of a direct association between vitamin D status and critical illness-related AI. However, our results do suggest that vitamin D deficiency exacerbates the effect of AI on cardiovascular stability in critically ill children.
    The Journal of clinical endocrinology and metabolism 04/2013; · 6.50 Impact Factor
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    ABSTRACT: Available from: http://ww2.aievolution.com/acm1301/index.cfm?do=abs.viewAbs&abs=1312
    American College of Genetics and Genomics Annual Meeting; 03/2013
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    ABSTRACT: BACKGROUND:: Vitamin D is recognized as a pleiotropic hormone important for the functioning of organ systems, including those central to critical illness pathophysiology. Recent studies have reported associations between vitamin D status and outcome among critically ill adults and children. Preoperative vitamin D status, impact of operative techniques, and relationship between immediate postoperative vitamin D levels and clinical course have not been described in the pediatric congenital heart disease (CHD) population. The objective of this study was to describe the impact of CHD surgery on vitamin D status and relationship between postoperative levels and clinical course. METHODS:: A prospective cohort study was conducted from 2009 to 2011 at a single tertiary care pediatric hospital. A total of 58 children with CHD were enrolled and blood collected preoperatively, intraoperatively, and postoperatively. Serum 25-hydroxyvitamin D (25OHD) was measured using liquid chromatography-mass spectrometry. RESULTS:: The mean preoperative 25OHD was 58.0 nM (SD, 22.4), with 42% being deficient (<50 nM). Postoperatively, we identified a 40% decline in 25OHD to 34.2 nM (SD, 14.5) with 86% being deficient. Intraoperative measurements determined that initiation of cardiopulmonary bypass coincided with abrupt decline. CHD patients requiring catecholamines had lower postoperative 25OHD (38.2 vs. 26.5 nM, P = 0.007), findings confirmed through multivariate logistic regression. Lower postoperative 25OHD was associated with increased fluid requirements and intubation duration. CONCLUSIONS:: Most CHD patients are vitamin-D deficient postoperatively due to low preoperative levels and a significant intraoperative decline. Interventional studies will be required to determine whether prevention of postoperative vitamin D deficiency improves outcome.
    Anesthesiology 03/2013; · 5.16 Impact Factor
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    ABSTRACT: OBJECTIVES: Newborn bloodspot screening (NBS) panels have expanded to include conditions for which treatment effects are less certain, creating debate about population-based screening criteria. We investigated Canadian public expectations and values regarding the types of conditions that should be included in NBS and whether parents should provide consent. METHODS: Eight focus groups (FG; n = 60) included education, deliberative discussion and pre-/post-questionnaires. Data were analysed quantitatively and qualitatively. RESULTS: Quantitatively, the majority supported NBS for serious disorders for which treatment is not available (95-98, 82%). A majority endorsed screening without explicit consent (77-88%) for treatable disorders, but 62% supported unpressured choice for screening for untreatable disorders. Qualitatively, participants valued treatment-related benefits for infants and informational benefits for families. Concern for anxiety, stigma and unwanted knowledge depended upon disease context and strength of countervailing benefits. CONCLUSIONS: Anticipated benefits of expanded infant screening were prioritized over harms, with information provision perceived as a mechanism for mitigating harms and enabling choice. However, we urge caution around the potential for public enthusiasm to foster unlimited uptake of infant screening technologies.
    Health expectations: an international journal of public participation in health care and health policy 02/2013; · 1.80 Impact Factor
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    Dataset: gim2012153a
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    ABSTRACT: Across all areas of health care, decision makers are in pursuit of what Berwick and colleagues have called the "triple aim": improving patient experiences with care, improving health outcomes, and managing health system impacts. This is challenging in a rare disease context, as exemplified by inborn errors of metabolism. There is a need for evaluative outcomes research to support effective and appropriate care for inborn errors of metabolism. We suggest that such research should consider interventions at both the level of the health system (e.g., early detection through newborn screening, programs to provide access to treatments) and the level of individual patient care (e.g., orphan drugs, medical foods). We have developed a practice-based evidence framework to guide outcomes research for inborn errors of metabolism. Focusing on outcomes across the triple aim, this framework integrates three priority themes: tailoring care in the context of clinical heterogeneity; a shift from "urgent care" to "opportunity for improvement"; and the need to evaluate the comparative effectiveness of emerging and established therapies. Guided by the framework, a new Canadian research network has been established to generate knowledge that will inform the design and delivery of health services for patients with inborn errors of metabolism and other rare diseases.Genet Med advance online publication 6 December 2012Genetics in Medicine (2012); doi:10.1038/gim.2012.153.
    Genetics in medicine: official journal of the American College of Medical Genetics 12/2012; · 3.92 Impact Factor
  • 2012 Joint ICBDSR / CCASN Meeting; 10/2012
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    ABSTRACT: Purpose:Effective parental education about newborn blood-spot screening may facilitate prompt follow-up, reduce psychosocial harms, and promote trust in screening programs. However, little is known about the aspects of education delivery and content that are of most importance for fostering understanding and meeting parental expectations. We aimed to identify elements of newborn blood-spot screening education and their associations with mothers' knowledge and satisfaction levels.Methods:We conducted a survey (by mail) of 1,712 mothers who were residing in Ontario, Canada, and whose infants had recently undergone newborn blood-spot screening.Results:We received 750 completed questionnaires (response rate 47%). Factors associated with respondents' higher knowledge of newborn blood-spot screening were higher level of education (odds ratio = 2.79), English being spoken at home (odds ratio = 1.96), receiving an information sheet at the time of newborn blood-spot screening (odds ratio = 1.57), and receiving information about how to interpret the results (odds ratio = 2.65). Factors associated with being satisfied were: receiving information prenatally (odds ratio = 2.35), from a health-care professional (odds ratio = 4.54), or from an information sheet at the time of newborn blood-spot screening (odds ratio = 1.72); and receiving messages about the purpose of screening (odds ratio = 3.78), the communication process (odds ratio = 2.57), the interpretation of the results (odds ratio = 4.19), and sample-handling methods (odds ratio = 3.13).Conclusion:Promoting mothers' understanding and meeting their expectations with respect to education about newborn blood-spot screening may require greater engagement with prenatal providers. It also calls for a greater emphasis on communicating with mothers about how blood samples are handled and about the meaning of the test results.Genet Med advance online publication 16 August 2012.
    Genetics in medicine: official journal of the American College of Medical Genetics 08/2012; · 3.92 Impact Factor
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    ABSTRACT: Vitamin D is a pleiotropic hormone important for the proper functioning of multiple organ systems. It has been hypothesized that vitamin D deficiency could contribute to or worsen outcomes in critical illness. The study objective was to determine the prevalence of vitamin D deficiency, risk factors for its presence, and potential association with clinically relevant outcomes in critically ill children. A prospective cohort study, conducted from 2005 to 2008 in 6 tertiary-care PICUs in Canada. Data and biological samples from 326 critically ill children up to 17 years of age were available for analysis. Total serum 25 hydroxyvitamin D or 25(OH)D was measured by using liquid chromatography-mass spectrometry. The prevalence of 25(OH)D <50 nmol/L was 69% (95% confidence interval, 64-74), and 23% (95% confidence interval, 19-28) for 25(OH)D between 50 to 75 nmol/L. Lower levels were associated with hypocalcemia, catecholamine utilization, and significant fluid bolus administration. Vitamin D deficiency was independently associated with a longer PICU length of stay (+1.92 days, P = .03) and increasing severity of illness as determined by the Pediatric Risk of Mortality score with every additional point increasing the likelihood of being vitamin D deficient by 8% (P = .005). This study provides evidence that vitamin D deficiency is both common among critically ill children and associated with greater severity of critical illness. Further research will determine whether targeted vitamin D supplementation or rapid restoration will improve outcome.
    PEDIATRICS 08/2012; 130(3):429-36. · 4.47 Impact Factor
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    ABSTRACT: The incidence of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) was estimated using the Canadian Paediatric Surveillance Program (CPSP) in Canada over a three-year period. Data regarding mutations associated with MCADD cases were collected wherever available. Data were collected over a 36-month period using a monthly mailed questionnaire distributed through the CPSP to more than 2500 Canadian paediatricians, medical geneticists and paediatric pathologists. During the three years of MCADD surveillance, 46 confirmed cases out of a total of 71 reported cases were found - an average of approximately 15 cases per year. This rate is lower than the initial estimate of approximately 30 cases per year of MCADD in Canada, based on the reported incidence of MCADD in the literature of approximately one in 10,000 to one in 20,000. All cases ascertained by newborn screening were asymptomatic. There were two deaths, both in jurisdictions without newborn screening for MCADD. The data support population-based newborn screening for MCADD.
    Paediatrics & child health 04/2012; 17(4):185-9. · 1.03 Impact Factor
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    ABSTRACT: Dried blood spot (DBS) samples on filter paper are surging in popularity as a sampling and storage vehicle for a wide range of clinical and pharmaceutical applications. For example, a DBS sample is collected from every baby born in the province of Ontario, Canada, for quantification of approximately one hundred analytes that are used to screen for 28 conditions, including succinylacetone (SA), a marker for hepatorenal tyrosinemia. Unfortunately, the conventional methods used to evaluate DBS samples for newborn screening and other applications are tedious and slow, with limited options for automated analysis. In response to this challenge, we have developed a method to couple digital microfluidics (DMF) to nanoelectrospray ionization mass spectrometry (nESI-MS) for SA quantification in DBS samples. The new system is formed by sandwiching a pulled glass capillary emitter between the two DMF substrates such that the capillary emitter is immobilized without external seals or gaskets. Moreover, we introduce a new feedback control system that enables high-fidelity droplet manipulation across DBS samples without manual intervention. The system was validated by application to on-chip extraction, derivatization, and analysis of SA and other analytes from DBS samples, with comparable performance to gold-standard methods. We propose that the new methods described here can potentially contribute to a new generation of analytical techniques for quantifying analytes in DBS samples for a wide range of applications.
    Analytical Chemistry 03/2012; 84(8):3731-8. · 5.70 Impact Factor

Publication Stats

141 Citations
108.76 Total Impact Points

Institutions

  • 2009–2013
    • The Children’s Hospital of Eastern Ontario
      Ottawa, Ontario, Canada
  • 2012
    • University of Toronto
      • Institute of Health Policy, Management and Evaluation
      Toronto, Ontario, Canada
  • 2008–2012
    • University of Ottawa
      • • Department of Epidemiology and Community Medicine
      • • Department of Medicine
      Ottawa, Ontario, Canada
  • 2008–2011
    • Children's Hospital of Eastern Ontario
      Ottawa, Ontario, Canada