Overview

The Subbarao Lab facilities support translational science by integrating clinical research in lung function testing, wet lab for processing of biological specimens, and a dry lab for biostatistics and epidemiology.

Research pursued in the Subbarao Lab is varies. The Lab actively contributes research to, and leverages the data from, clinical studies such as The CHILD Cohort Study. The Lab is also participating in numerous research projects supported by various granting agencies. Among these, most central to the Lab’s current work is the project “Disentangling ChildHOOD Asthma,” supported by Dr. Subbarao’s Tier 1 Canada Research Chair in Paediatric Asthma and Lung Health (2020-2027). The Lab’s capabilities in conducting specialized lung function tests figures centrally in its contributions to research across these projects and clinical studies.

Specialized lung function measures and clinical assessments are performed on children of all ages by clinical and research personnel.

Multidisciplinary training to facilitate team science: Trainees in the Subbarao Lab come from diverse backgrounds in medicine, physiology, biostatistics and epidemiology. They interact collaboratively with clinical staff and other labs in order to achieve integrated multidisciplinary research projects. Students of all backgrounds are encouraged to expand their training in all parts of the research program from clinical assessment to statistical analyses.

Disentangling CHILDhood Asthma

asthma inhalher with swirling rainbow pattern behind

Canada Research Chair in Paediatric Asthma and Lung Health (2020-2027)

PI: Dr. Subbarao

Dr. Subbarao’s world-leading research program, supported by her Tier 1 Canada Research Chair in Paediatric Asthma and Lung Health (2020-2027), aims to disentangle preschool wheeze syndromes, provide tools for use in infants to precisely diagnose asthma subtype, monitor lung growth and response to therapy at the individual level and provide novel insights into the risk and protective factors associated with each asthma subtype.  The discovery of novel causal associations will be further explored through targeted translational research collaborations paving the way for novel prevention strategies to eradicate asthma subtypes with precision.

Asthma affects 1 in 7 children leading to poor lung growth, cardiovascular disease and premature death.  Current therapies, effective at controlling symptoms, do not prevent the lung function loss associated with asthma. Dr. Subbarao’s program integrates longitudinal lung function measures from infancy, with genetics and exposure measurement to impact standard clinical care of paediatric asthma.  Her transformative program will (1) Develop tools to diagnose asthma subtype from infancy. (2) Identify causal risk factors associated with each asthma subtype to develop prevention strategies. (3) Produce lung function tests to monitor therapy aimed at preserving lung function from infancy.

Dr. Subbarao’s clinical research laboratory has generated an unprecedented pool of longitudinal lung function data from infancy to age 8 years in the CHILD study.  Biostatisticians in the dry lab have developed and refined methodologies to model these lung function measures from infancy.   She will use different approaches to discover novel subtypes of asthma and lung growth patterns in aims 1 and 2.  In aim 3, she will integrate these novel subtypes with ‘omics’ to discover key biological risk factors.

Aim 1 – A multi-trajectory model using lung function to discover novel asthma subtypes.

Using data from the CHILD study to age 8 years, her lab will use a multi-trajectory model of wheeze symptoms with lung function growth, atopic sensitization, anthropometrics to describe patterns of co-development symptoms and measures.  Trajectories of each trait: wheeze symptom, atopic sensitization and lung function have already been modelled from infancy to 5 years.  Patterns in these single traits have already provided novel insights.  For example, rapid weight gain in the first year of life doubles the risk of asthma diagnosis at age 5 years, the persistent atopic sensitization from age 1 to age 3 years increases the risk for asthma diagnosis at age 5 years by 11-fold. Patterns identified using the novel multi-trajectory models will be compared to previous simpler models of single trait for their association with 8-year asthma diagnosis.

Aim 2 – A multi-trajectory model using lung function to discover novel asthma subtypes.

Most infant lung function studies are small (<100 subjects) with sparse early life measures (only 1 measure in first 5 years) and poor longitudinal follow-up (90 to age 5 years).  Furthermore, over 80% of the multiple breath washout measures performed in infants produced acceptable interpretable LCI values.

Aim 3 – Integration of ‘Omics’ with newly discovered asthma subtypes and growth patterns.

The CHILD Cohort Study has data collected from the analysis of nasal and gut microbiome, genetic polymorphisms, viral assays and environmental exposures. Dr. Subbarao will lead the integration of this rich ‘omics’ dataset with asthma subtypes in Aim 1 and growth patterns from Aim 2.

Anticipated Impacts

  • Clinical:  Generation of an accurate biomarker-based (e.g., Genetic risk score) prediction tool specific to each asthma subtype.
  • Translation Research:  Dr. Subbarao will use the discovery of these novel causal factors to actively engage basic scientists and enable translational research for the discovery of novel precise asthma subtype therapeutic targets.

Treatments directed towards airway inflammation and symptom control do not impact lung function loss.  There is considerable debate whether treatments aimed at airway responsiveness could protect against lung function loss. Limited data suggests that early initiation of combination therapy within 2 years of symptom onset may prevent lung function loss with asthma. Dr. Subbarao’s team has developed tools that can earlier detect obstructive lung disease in infants and preschool children.  She has shown that although Lung Clearance Index (LCI) is responsive and improves with recovery after acute exacerbation; abnormalities in LCI can persist in 50% of children who have fully recovered and are asymptomatic clinically. It is unclear whether these changes are fixed or reparable with appropriate therapy. To assess the utility of LCI as a clinical objective measure for preschool asthma clinical trials, Dr. Subbarao will conduct a pilot randomized controlled study of a combination inhaled steroid/long-acting bronchodilator in preschool children with LCI abnormalities after recovery from acute wheezing exacerbation. She will validate this model using a known therapeutic and then use this model to test other more novel biologic therapies.

Anticipated impacts

  • Clinical: The generation of a preschool asthma clinical trial model will revolutionize our ability to evaluate novel therapeutics in young children objectively. This will increase our therapeutic options for this age group. It will also radically alter the management of infant wheeze by targeting therapy to maintain or improve lung growth in addition to symptoms – thereby preventing asthma and promoting lifelong lung health.

Clinical Asthma Studies

blue circle with white silhouette of person using an inhaler

Active Studies

The CHILD Cohort Study is a prospective longitudinal birth cohort study investigating the genetic and environmental factors that influence various aspects of health and disease (including asthma) in childhood and beyond. Dr. Subbarao co-designed and built the Study and in 2017 became its Director.

CHILD is one of the largest, most deeply phenotyped national studies of asthma in the world, recognized for its innovation and attention to detailed environmental assessment paired with deep physiologic and biologic phenotyping. It has already generated many insights into early-life factors influencing the development of asthma.  To date, more than a dozen CIHR team projects are dependent on this cohort’s data and biorepository.

CHILD researchers are actively following the Study participants over time as they grow and develop—from mid-pregnancy into childhood and adolescence. CHILD is designed this way so it can collect information at time points that are considered to be especially critical to the health and development of children. By following the children prospectively as they grow, as opposed to retrospectively, CHILD researchers are able to more accurately learn about how different early-life exposures relate to health and disease outcomes.

Almost 3500 families are participating in the Study, in four sites across Canada. Questionnaires, home environment assessments, clinical assessments, and biological sample collection are the main measures employed to explore the exposures that can lead to health and disease.

CHILD findings will influence medical practice, parenting choices, consumer product regulation and policy development—from building codes and household purchasing behaviours to decisions about childbirth and delivery, diet , breastfeeding, cleaning products used in homes, owning a family pet and dealing with stress.

CHILD is the largest multidisciplinary, longitudinal, population-based birth cohort study in Canada and is designed to be one of the most informative studies of its kind in the world.

The Toronto CHILD site investigators are especially interested in respiratory health and the connection to other conditions such as allergy and eczema. As part of the on-site testing at The Hospital for Sick Children, several lung function tests are used to investigate quantitative measure of lung health. Earlier diagnosis of respiratory issues can lead to better health outcomes for children.

Research Methods

  • Lung Function Tests:
    • Spirometry
    • Multiple Breath Washout (MBW)
    • Exhaled Nitric Oxide (eNO)
    • Forced Oscillation Technique (FOT)
  • Child’s Biological Samples:
    • Blood
    • Urine
    • Stool
    • Nasal swab
    • Teeth
  • Questionnaires about:
    • Child’s medical, behavioral, and nutritional health
    • Parent physical and mental health
    • Indoor and outdoor home environment
  • Allergy skin prick test
  • Clinical assessment by a health care professional

Anticipated impacts

  • Achieve a deeper understanding of the influence of indoor and outdoor environment on health and disease
  • Inform personalized medical practice, parenting choices, consumer product regulations and policy development for healthy communities
  • Contribute to the development of new diagnostics and therapies, and of better health management and prevention strategies for a variety of chronic diseases in young children

The DIVA study (Vitamin D In the prevention of Viral-induced Asthma in preschoolers) is a 7-month intensive multicenter, triple-blind, randomized, parallel-group, placebo-controlled trial of vitamin D3 supplementation and its effect on asthma.

Children aged 1-5 (<6) years with physician-diagnosed asthma predominantly triggered by upper respiratory tract infection (URTI) will be screened for enrolment in paediatric asthma, respiratory or allergy clinics and the Emergency Department (ED) and randomized between Sept 1 to January 31, annually. Eligible participants enrolled in the study will receive a high dose of vitamin D or a placebo every 3.5 months during their usual clinic visit, and a daily supplement of vitamin D or a placebo. This study will test whether children in vitamin D group have less frequent and less severe asthma exacerbations compared with those receiving placebo. The study will also document the safety profile of this strategy.

Participants will be followed for 7 months, with 3 visits every 3.5 months with repeated urine (for calcium:creatinine ratio) and blood samples. In addition, ten (10) days after each bolus, urine will be sampled for urinary calcium:creatinine ratio. In case of elevated urine calcium:creatinine ratio, a blood sample may be needed primarily for markers of calcium metabolism and exploratory outcomes. There will be 6 follow-up phone calls, at week 1 and then monthly, to inquire about exacerbations and URTIs, remind parents to complete questionnaires and to collect a nasal swab at each exacerbation and screen for adverse events.

The main outcome is the number of courses of rescue oral corticosteroids (OCS) per child during the study period. Several secondary outcomes will be documented using biological samples and validated questionnaires to determine laboratory-confirmed respiratory infections, intensity and severity of exacerbations, mean number of ED visits, parents’ functional status during exacerbations, de-intensification of preventive asthma therapy, cost effectiveness, and safety profile.

Research Methods

  • Lung Function Tests:
    • Forced Oscillation Technique (FOT) – only in children >3 years of age
  • Child’s Biological Samples:
    • Blood
    • Urine
    • Nasal swab
  • Questionnaires about:
    • Child’s health
    • Asthma control
    • Parental impact of illness
    • Dietary intake (particularly calcium and vitamin D)
    • Sun exposure

Anticipated impacts

  • Inform whether vitamin D supplements given during the fall and winter months can reduce the frequency and severity of asthma flare-ups triggered by colds in preschool-aged children
  • Influence the management of URTI-induced asthma in high-morbidity preschoolers
  • Enable identification of children with greatest benefit and understanding of vitamin D modulation of immune/inflammatory response
  • Add to accumulating safety data in preschoolers

Past Studies

Wheezy ER was a prospective study with a cohort of preschool children with severe asthma.

Study participants were all seen in the Emergency Department (ED) at The Hospital for Sick Children due to acute wheeze. The Wheezy ER study team strove to better comprehend the unique characteristics of this severe asthma and wheeze cohort to better prevent and treat this population. A main objective of this study was to determine which lung function tests and clinical parameters can distinguish healthy preschool children from those with severe wheeze.

The Wheezy ER team completed on-site visits at SickKids within 5 days of the child being discharged from the ED. The measurements collected when the child was ill were compared to those of the same child 3 months later, allowing the unique ability to better understand, define, and predict when and why these acute wheeze episodes occur.

The Wheezy ER Study completed follow-up in November 2018. The study demonstrated that pulmonary function test (PFT) outcomes are abnormal in a significant number of preschool children with wheezing three months post-ED visit for acute wheeze exacerbation. This suggests that PFT outcomes could provide additional insight into preschool asthma control beyond symptom assessment alone.

Research Methods

  • Lung Function Tests:
    • Spirometry
    • Multiple Breath Washout (MBW)
    • Forced Oscillation Technique (FOT)
  • Child’s Biological Samples:
    • Blood
    • Urine
    • Nasal swab
    • Nasal brush
  • Questionnaires about:
    • Child’s health
    • Child’s sleep
    • Parental health
    • Asthma control
  • Allergy skin prick test
  • Clinical assessment by a health care professional

Anticipated impacts

  • Improve prevention strategies relating to severe asthma and wheeze
  • Inform monitoring and treatment protocols for preschool children with severe wheeze and asthma
  • Define phenotypes to better portray the various types of preschool “asthma”

Lung Function Tests

The Subbarao Lab facilities include a clinical research laboratory for lung function, where specialized lung function measures and clinical assessments are performed in children of all ages by clinical personnel and research assistants.

The lung function tests performed in the Subbarao Lab are categorized as tests for infants only (Infant Pulmonary Function Test); tests for school-aged children only (spirometry, Forced Oscillation Technique); and tests for both infants and school-aged children (Multiple Breath Washout, Exhaled Nitric Oxide).

Infant Pulmonary Function Test (iPFT)

iPFT’s are a means of helping to define respiratory disease in infants, since they are unable to perform traditional tests. Before the iPFT, the infant is given medication that puts them into a light sleep in order to properly perform these breathing maneuvers. The care team can then evaluate the child’s lung volume and flow measurements.

Spirometry

This is an effort-based test which measures air flow in the lungs. It is a commonly used lung function tests used in clinical settings for screening. The child performs a maximal expiration; blowing a breath out as hard and as long as possible. Visual incentives (e.g., blowing out birthday candles) are often added as motivation tools.

Forced Oscillation Technique (FOT)

FOT measures lung resistance and elastance. The machine gently emits oscillations at various frequencies during normal tidal breathing. Each trial is roughly 16 seconds of oscillations, making this is a quick test.

Multiple Breath Washout (MBW)

MBW measures the efficiency of gas mixing in the lungs. It has been proven to be useful in asthma, cystic fybrosis, and other obstructive respiratory disease populations. Only normal tidal breathing is required while gases are temporarily washed out of the lungs.

Exhaled Nitric Oxide (eNO)

This test measures the level of nitric oxide (NO) gas in the lungs; a marker of inflammation. It is a single breath maneuver of near total lung capacity (TLC) exhaled over several seconds. There is a video game-like format to encourage paediatric participants.

Funded Grants

The Subbarao Lab participates in numerous research projects supported by various granting agencies.

The table below lists research projects in which the Subbarao Lab is currently participating. It can be searched, or sorted by any column.

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