BACKGROUND & AIMS Establishment of the gastrointestinal microbiota during infancy affects imm... more BACKGROUND & AIMS Establishment of the gastrointestinal microbiota during infancy affects immune system development and oral tolerance induction. Perturbations in the microbiome during this period can contribute to development of immune-mediated diseases. We monitored microbiota maturation and associations with subsequent development of allergies in infants and children. METHODS We collected 1453 stool samples, at 5, 13, 21 and 31 weeks post-partum (infants), and once at school-age (6-11 years), from 440 children (49.3% girls, 24.8% born by caesarean section; all children except for 6 were breastfed for varying durations; median 40 weeks; interquartile range, 30-53 weeks). Microbiota were analyzed by amplicon sequencing. Children were followed through 3 years of age for development of atopic dermatitis; data on allergic sensitization and asthma were collected when children were school age. RESULTS Diversity of fecal microbiota, assessed by Shannon index, did not differ significantly among children from 5 through 13 weeks after birth, but thereafter gradually increased to 21 and 31 weeks. Most bacteria within the Bacteroidetes and Proteobacteria phyla were already present at 5 weeks after birth, whereas many bacteria of the Firmicutes phylum were acquired at later times in infancy. At school age, many new Actinobacteria, Firmicutes, and Bacteroidetes bacterial taxa emerged. The largest increase in microbial diversity occurred after 31 weeks. Vaginal, compared with cesarean section delivery, was most strongly associated with an enrichment of Bacteroides species at 5 weeks through 31 weeks. From 13 weeks onwards, diet became most important determinant of microbiota composition-cessation of breastfeeding, rather than solid food introduction, was associated with changes. For example, Bifidobacteria, staphylococci, and streptococci significantly decreased upon cessation of breastfeeding, whereas bacteria within the Lachnospiraceae family (Pseudobutyrivibrio, Lachnobacterium, Roseburia, and Blautia) increased. When we adjusted for confounding factors, we found fecal microbiota composition to be associated with development of atopic dermatitis, allergic sensitization, and asthma. Members of the Lachnospiraceae family, as well as the genera Faecalibacterium and Dialister, were associated with a reduced risk of atopy. CONCLUSIONS In a longitudinal study of fecal microbiota of children from 5 weeks through 6-11 years, we tracked changes in diversity and composition associated with the development of allergies and asthma.
Clinical science (London, England : 1979), Jan 31, 2018
The activation of brown adipose tissue (BAT) is associated with reductions in circulating lipids ... more The activation of brown adipose tissue (BAT) is associated with reductions in circulating lipids and glucose in rodents and contributes to energy expenditure in humans indicating the potential therapeutic importance of targetting this tissue for the treatment of a variety of metabolic disorders. In order to evaluate the therapeutic potential of human BAT, a variety of methodologies for assessing the volume and metabolic activity of BAT are utilized. Cold exposure is often utilized to increase BAT activity but inconsistencies in the characteristics of the exposure protocols make it challenging to compare findings. The metabolic activity of BAT in response to cold exposure has most commonly been measured by static positron emission tomography of F-fluorodeoxyglucose in combination with computed tomography (F-FDG PET-CT) imaging, but recent studies suggest that under some conditions this may not always reflect BAT thermogenic activity. Therefore, recent studies have used alternative po...
To explore parents' recommendations to enhance enrollment in multidisciplinary clinical care ... more To explore parents' recommendations to enhance enrollment in multidisciplinary clinical care for managing pediatric obesity. Data for this interpretative description study were collected through individual, semistructured interviews that were audiorecorded, transcribed verbatim, and analyzed thematically. Parents (n = 79) were recruited from 4 multidisciplinary weight management clinics in Canada located in Edmonton, Hamilton, Montreal, and Vancouver. Most interviewed parents had children with obesity (body mass index ≥95th percentile; 84.2%), were female (87.3%), had postsecondary education (69.6%), and were white (75.9%). Parents' recommendations referred to enrollment opportunities, information about obesity services, motivation for treatment, and accessibility to obesity services. Specifically, parents recommended to increase referral options and follow-up contacts with families during the enrollment process, inform referring physicians and families about the availabilit...
Journal of child psychology and psychiatry, and allied disciplines, Jan 18, 2018
Individuals born extremely preterm are exposed to significant perinatal stresses that are associa... more Individuals born extremely preterm are exposed to significant perinatal stresses that are associated with an increased risk of psychopathology. However, a paucity of longitudinal studies has prevented the empirical examination of long-term, dynamic effects of perinatal adversity on mental health. Here, internalizing and externalizing problems from adolescence through adulthood were compared in individuals born at extremely low birth weight (ELBW; <1,000 g) and normal birth weight (NBW; >2,500 g). Internalizing and externalizing data were collected over 20 years in three waves, during adolescence, young adulthood, and adulthood. Growth models were used to compare longitudinal trajectories in a geographically based sample of 151 ELBW survivors and 137 NBW control participants born between 1977 and 1982 matched for age, sex, and socioeconomic status at age 8. After adjusting for sex, socioeconomic and immigrant status, and family functioning, ELBW survivors failed to show the nor...
Journal of applied physiology (Bethesda, Md. : 1985), Jan 21, 2017
Existing methods for diagnosing diabetes and for identifying risk of diabetes development are com... more Existing methods for diagnosing diabetes and for identifying risk of diabetes development are completed under resting conditions and based on adult data. Studying additional methods to identify metabolic risk in children is warranted. Our objective was to examine the validity and reliability of a metabolic flexibility (MetFlex) test for screening glycemia and insulin resistance (IR) in children. We hypothesized higher MetFlex during exercise would be correlated with lower fasting glucose and homeostasis model assessment of insulin resistance (HOMA-IR), and higher whole body insulin sensitivity index (WBISI) and insulin secretion-sensitivity index-2 (ISSI-2). Thirty-four children with obesity (14 boys, 20 girls) attended 2 visits. At visit 1, an OGTT was followed by anthropometric and aerobic fitness (V ̇O2max) assessments. Insulin and glucose during the OGTT were used to calculate HOMA-IR, WBISI and ISSI-2. At visit 2, a 13C-enriched carbohydrate drink was ingested before 60 min of ...
Early life microbial colonization and succession is critically important to healthy development w... more Early life microbial colonization and succession is critically important to healthy development with impacts on metabolic and immunologic processes throughout life. A longitudinal prospective cohort was recruited from midwifery practices to include infants born at full term gestation to women with uncomplicated pregnancies. Here we compare bacterial community succession in infants born vaginally, with no exposure to antibiotics (n = 53), with infants who were exposed to intrapartum antibiotic prophylaxis (IAP) for Group B Streptococcus (GBS; n = 14), and infants born by C-section (n = 7). Molecular profiles of the 16 S rRNA genes indicate that there is a delay in the expansion of Bifidobacterium, which was the dominate infant gut colonizer, over the first 12 weeks and a persistence of Escherichia when IAP for GBS exposure is present during vaginal labour. Longer duration of IAP exposure increased the magnitude of the effect on Bifidobacterium populations, suggesting a longer delay ...
Previous genome wide association studies (GWAS) identified associations of multiple common varian... more Previous genome wide association studies (GWAS) identified associations of multiple common variants with diastolic and systolic blood pressure traits in adults. However, the contribution of these loci to variations of blood pressure in early life is unclear. We assessed the child and parental contributions of 33 GWAS single-nucleotide polymorphisms (SNPs) for blood pressure in 1,525 participants (515 children, 406 mothers and 237 fathers) of the Family Atherosclerosis Monitoring In early life (FAMILY) study followed-up for 5 years. Two genotype scores for systolic (29 SNPs) and diastolic (24 SNPs) blood pressure were built. Linear mixed-effect regressions showed significant association between rs1378942 in CSK and systolic blood pressure (β = 0.98±0.46, P = 3.4×10-2). The child genotype scores for diastolic and systolic blood pressure were not associated in children. Nominally significant parental genetic effects were found between the SNPs rs11191548 (CYP17A1) (paternal, β = 2.78±1...
Birth weight is an indicator of newborn health and a strong predictor of health outcomes in later... more Birth weight is an indicator of newborn health and a strong predictor of health outcomes in later life. Significant variation in diet during pregnancy between ethnic groups in high-income countries provides an ideal opportunity to investigate the influence of maternal diet on birth weight. Four multiethnic birth cohorts based in Canada (the NutriGen Alliance). 3997 full-term mother-infant pairs of diverse ethnic groups who had principal component analysis-derived diet pattern scores-plant-based, Western and health-conscious-and birth weight data. No associations were identified between the Western and health-conscious diet patterns and birth weight; however, the plant-based dietary pattern was inversely associated with birth weight (β=-67.6 g per 1-unit increase; P<0.001), and an interaction with non-white ethnicity and birth weight was observed. Ethnically stratified analyses demonstrated that among white Europeans, maternal consumption of a plant-based diet associated with lowe...
The reasons for the increased risk of gestational diabetes among South Asian women are not well u... more The reasons for the increased risk of gestational diabetes among South Asian women are not well understood. We sought to identify the determinants of gestational diabetes and its impact on newborn health in a prospective birth cohort of South Asian women and their babies. As part of the South Asian Birth Cohort (START) prospective birth cohort study in Ontario, we recruited 1012 South Asian women with singleton pregnancies in the second trimester of pregnancy between July 11, 2011, and Nov. 10, 2015. We collected health information and physical measurements and administered an oral glucose tolerance test. Birth weight and skinfold thickness measurements were obtained from their newborns, and cord blood glucose and insulin levels were measured. The incidence of gestational diabetes was 36.3% (95% confidence interval [CI] 33.3%-39.3%); the age-standardized rate was 40.7%. Factors associated with gestational diabetes included maternal age (odds ratio [OR] 1.08 [95% CI 1.04-1.12]), fami...
Background -Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder l... more Background -Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder leading to premature atherosclerosis. Children with HeFH exhibit early signs of atherosclerosis, manifested by increased carotid intima-media thickness (IMT). In this study, we assessed the effect of 2-year treatment with rosuvastatin on carotid IMT in HeFH children. Methods -Children with HeFH (aged 6 to <18 years) and low-density lipoprotein cholesterol (LDL-C) >4.9 mmol/L or >4.1 mmol/L in combination with other risk factors, received rosuvastatin for 2 years, starting at 5 mg once daily, with up-titration to 10 mg (aged 6 to <10 years) or 20 mg (aged 10 to <18 years). Carotid IMT was assessed by ultrasonography at baseline, 12 and 24 months in all patients and in age-matched unaffected siblings. Carotid IMT was measured at 3 locations (common carotid artery, carotid bulb, internal carotid artery) in both the left and right carotid arteries. A linear mixed-effects model ...
Experts recommend that clinicians assess motivational factors before initiating care for pediatri... more Experts recommend that clinicians assess motivational factors before initiating care for pediatric obesity. Currently, there are no well-established clinical tools available for assessing motivation in youth with obesity or their families. This represents an important gap in knowledge since motivation-related information may shed light on which patients might fail to complete treatment programs. Our study was designed to evaluate the measurement properties and utility of the Readiness and Motivational Interview for Families (RMI-Family), a structured interview that utilizes a motivational interviewing approach to (i) assess motivational factors in youth and their parents, and (ii) examine the degree to which motivation and motivation-related concordance between youth and parents are related to making changes to lifestyle habits for managing obesity in youth. From 2016 to 2020, this prospective study will include youth with obesity (body mass index [BMI] ≥97th percentile; 13-17 years...
The effects of maternal prepregnancy body mass index (BMI) and gestational weight gain (GWG) on m... more The effects of maternal prepregnancy body mass index (BMI) and gestational weight gain (GWG) on maternal and offspring obesity traits, as well as the maternal and offspring genetic contribution to GWG and postpartum weight retention, were examined. Blood samples from mothers (n = 608) and offspring (n = 541) were genotyped for 83 BMI-associated SNPs and 47 waist-to-hip ratio (WHR)-associated SNPs. Linear regression and mixed-effects regression models were performed to examine clinical epidemiological and genetic associations with unweighted and weighted BMI and WHR genetic risk scores (GRS). Prepregnancy BMI was positively associated with offspring weight and BMI Z-score from birth to 5 years. GWG was positively associated with maternal postpartum weight retention at 1 and 5 years and with offspring weight Z-score from birth to 5 years old. The maternal unweighted BMI GRS was associated with prepregnancy BMI, postpartum weight retention at 5 years, and offspring weight Z-score from ...
BACKGROUND & AIMS Establishment of the gastrointestinal microbiota during infancy affects imm... more BACKGROUND & AIMS Establishment of the gastrointestinal microbiota during infancy affects immune system development and oral tolerance induction. Perturbations in the microbiome during this period can contribute to development of immune-mediated diseases. We monitored microbiota maturation and associations with subsequent development of allergies in infants and children. METHODS We collected 1453 stool samples, at 5, 13, 21 and 31 weeks post-partum (infants), and once at school-age (6-11 years), from 440 children (49.3% girls, 24.8% born by caesarean section; all children except for 6 were breastfed for varying durations; median 40 weeks; interquartile range, 30-53 weeks). Microbiota were analyzed by amplicon sequencing. Children were followed through 3 years of age for development of atopic dermatitis; data on allergic sensitization and asthma were collected when children were school age. RESULTS Diversity of fecal microbiota, assessed by Shannon index, did not differ significantly among children from 5 through 13 weeks after birth, but thereafter gradually increased to 21 and 31 weeks. Most bacteria within the Bacteroidetes and Proteobacteria phyla were already present at 5 weeks after birth, whereas many bacteria of the Firmicutes phylum were acquired at later times in infancy. At school age, many new Actinobacteria, Firmicutes, and Bacteroidetes bacterial taxa emerged. The largest increase in microbial diversity occurred after 31 weeks. Vaginal, compared with cesarean section delivery, was most strongly associated with an enrichment of Bacteroides species at 5 weeks through 31 weeks. From 13 weeks onwards, diet became most important determinant of microbiota composition-cessation of breastfeeding, rather than solid food introduction, was associated with changes. For example, Bifidobacteria, staphylococci, and streptococci significantly decreased upon cessation of breastfeeding, whereas bacteria within the Lachnospiraceae family (Pseudobutyrivibrio, Lachnobacterium, Roseburia, and Blautia) increased. When we adjusted for confounding factors, we found fecal microbiota composition to be associated with development of atopic dermatitis, allergic sensitization, and asthma. Members of the Lachnospiraceae family, as well as the genera Faecalibacterium and Dialister, were associated with a reduced risk of atopy. CONCLUSIONS In a longitudinal study of fecal microbiota of children from 5 weeks through 6-11 years, we tracked changes in diversity and composition associated with the development of allergies and asthma.
Clinical science (London, England : 1979), Jan 31, 2018
The activation of brown adipose tissue (BAT) is associated with reductions in circulating lipids ... more The activation of brown adipose tissue (BAT) is associated with reductions in circulating lipids and glucose in rodents and contributes to energy expenditure in humans indicating the potential therapeutic importance of targetting this tissue for the treatment of a variety of metabolic disorders. In order to evaluate the therapeutic potential of human BAT, a variety of methodologies for assessing the volume and metabolic activity of BAT are utilized. Cold exposure is often utilized to increase BAT activity but inconsistencies in the characteristics of the exposure protocols make it challenging to compare findings. The metabolic activity of BAT in response to cold exposure has most commonly been measured by static positron emission tomography of F-fluorodeoxyglucose in combination with computed tomography (F-FDG PET-CT) imaging, but recent studies suggest that under some conditions this may not always reflect BAT thermogenic activity. Therefore, recent studies have used alternative po...
To explore parents' recommendations to enhance enrollment in multidisciplinary clinical care ... more To explore parents' recommendations to enhance enrollment in multidisciplinary clinical care for managing pediatric obesity. Data for this interpretative description study were collected through individual, semistructured interviews that were audiorecorded, transcribed verbatim, and analyzed thematically. Parents (n = 79) were recruited from 4 multidisciplinary weight management clinics in Canada located in Edmonton, Hamilton, Montreal, and Vancouver. Most interviewed parents had children with obesity (body mass index ≥95th percentile; 84.2%), were female (87.3%), had postsecondary education (69.6%), and were white (75.9%). Parents' recommendations referred to enrollment opportunities, information about obesity services, motivation for treatment, and accessibility to obesity services. Specifically, parents recommended to increase referral options and follow-up contacts with families during the enrollment process, inform referring physicians and families about the availabilit...
Journal of child psychology and psychiatry, and allied disciplines, Jan 18, 2018
Individuals born extremely preterm are exposed to significant perinatal stresses that are associa... more Individuals born extremely preterm are exposed to significant perinatal stresses that are associated with an increased risk of psychopathology. However, a paucity of longitudinal studies has prevented the empirical examination of long-term, dynamic effects of perinatal adversity on mental health. Here, internalizing and externalizing problems from adolescence through adulthood were compared in individuals born at extremely low birth weight (ELBW; <1,000 g) and normal birth weight (NBW; >2,500 g). Internalizing and externalizing data were collected over 20 years in three waves, during adolescence, young adulthood, and adulthood. Growth models were used to compare longitudinal trajectories in a geographically based sample of 151 ELBW survivors and 137 NBW control participants born between 1977 and 1982 matched for age, sex, and socioeconomic status at age 8. After adjusting for sex, socioeconomic and immigrant status, and family functioning, ELBW survivors failed to show the nor...
Journal of applied physiology (Bethesda, Md. : 1985), Jan 21, 2017
Existing methods for diagnosing diabetes and for identifying risk of diabetes development are com... more Existing methods for diagnosing diabetes and for identifying risk of diabetes development are completed under resting conditions and based on adult data. Studying additional methods to identify metabolic risk in children is warranted. Our objective was to examine the validity and reliability of a metabolic flexibility (MetFlex) test for screening glycemia and insulin resistance (IR) in children. We hypothesized higher MetFlex during exercise would be correlated with lower fasting glucose and homeostasis model assessment of insulin resistance (HOMA-IR), and higher whole body insulin sensitivity index (WBISI) and insulin secretion-sensitivity index-2 (ISSI-2). Thirty-four children with obesity (14 boys, 20 girls) attended 2 visits. At visit 1, an OGTT was followed by anthropometric and aerobic fitness (V ̇O2max) assessments. Insulin and glucose during the OGTT were used to calculate HOMA-IR, WBISI and ISSI-2. At visit 2, a 13C-enriched carbohydrate drink was ingested before 60 min of ...
Early life microbial colonization and succession is critically important to healthy development w... more Early life microbial colonization and succession is critically important to healthy development with impacts on metabolic and immunologic processes throughout life. A longitudinal prospective cohort was recruited from midwifery practices to include infants born at full term gestation to women with uncomplicated pregnancies. Here we compare bacterial community succession in infants born vaginally, with no exposure to antibiotics (n = 53), with infants who were exposed to intrapartum antibiotic prophylaxis (IAP) for Group B Streptococcus (GBS; n = 14), and infants born by C-section (n = 7). Molecular profiles of the 16 S rRNA genes indicate that there is a delay in the expansion of Bifidobacterium, which was the dominate infant gut colonizer, over the first 12 weeks and a persistence of Escherichia when IAP for GBS exposure is present during vaginal labour. Longer duration of IAP exposure increased the magnitude of the effect on Bifidobacterium populations, suggesting a longer delay ...
Previous genome wide association studies (GWAS) identified associations of multiple common varian... more Previous genome wide association studies (GWAS) identified associations of multiple common variants with diastolic and systolic blood pressure traits in adults. However, the contribution of these loci to variations of blood pressure in early life is unclear. We assessed the child and parental contributions of 33 GWAS single-nucleotide polymorphisms (SNPs) for blood pressure in 1,525 participants (515 children, 406 mothers and 237 fathers) of the Family Atherosclerosis Monitoring In early life (FAMILY) study followed-up for 5 years. Two genotype scores for systolic (29 SNPs) and diastolic (24 SNPs) blood pressure were built. Linear mixed-effect regressions showed significant association between rs1378942 in CSK and systolic blood pressure (β = 0.98±0.46, P = 3.4×10-2). The child genotype scores for diastolic and systolic blood pressure were not associated in children. Nominally significant parental genetic effects were found between the SNPs rs11191548 (CYP17A1) (paternal, β = 2.78±1...
Birth weight is an indicator of newborn health and a strong predictor of health outcomes in later... more Birth weight is an indicator of newborn health and a strong predictor of health outcomes in later life. Significant variation in diet during pregnancy between ethnic groups in high-income countries provides an ideal opportunity to investigate the influence of maternal diet on birth weight. Four multiethnic birth cohorts based in Canada (the NutriGen Alliance). 3997 full-term mother-infant pairs of diverse ethnic groups who had principal component analysis-derived diet pattern scores-plant-based, Western and health-conscious-and birth weight data. No associations were identified between the Western and health-conscious diet patterns and birth weight; however, the plant-based dietary pattern was inversely associated with birth weight (β=-67.6 g per 1-unit increase; P<0.001), and an interaction with non-white ethnicity and birth weight was observed. Ethnically stratified analyses demonstrated that among white Europeans, maternal consumption of a plant-based diet associated with lowe...
The reasons for the increased risk of gestational diabetes among South Asian women are not well u... more The reasons for the increased risk of gestational diabetes among South Asian women are not well understood. We sought to identify the determinants of gestational diabetes and its impact on newborn health in a prospective birth cohort of South Asian women and their babies. As part of the South Asian Birth Cohort (START) prospective birth cohort study in Ontario, we recruited 1012 South Asian women with singleton pregnancies in the second trimester of pregnancy between July 11, 2011, and Nov. 10, 2015. We collected health information and physical measurements and administered an oral glucose tolerance test. Birth weight and skinfold thickness measurements were obtained from their newborns, and cord blood glucose and insulin levels were measured. The incidence of gestational diabetes was 36.3% (95% confidence interval [CI] 33.3%-39.3%); the age-standardized rate was 40.7%. Factors associated with gestational diabetes included maternal age (odds ratio [OR] 1.08 [95% CI 1.04-1.12]), fami...
Background -Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder l... more Background -Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder leading to premature atherosclerosis. Children with HeFH exhibit early signs of atherosclerosis, manifested by increased carotid intima-media thickness (IMT). In this study, we assessed the effect of 2-year treatment with rosuvastatin on carotid IMT in HeFH children. Methods -Children with HeFH (aged 6 to <18 years) and low-density lipoprotein cholesterol (LDL-C) >4.9 mmol/L or >4.1 mmol/L in combination with other risk factors, received rosuvastatin for 2 years, starting at 5 mg once daily, with up-titration to 10 mg (aged 6 to <10 years) or 20 mg (aged 10 to <18 years). Carotid IMT was assessed by ultrasonography at baseline, 12 and 24 months in all patients and in age-matched unaffected siblings. Carotid IMT was measured at 3 locations (common carotid artery, carotid bulb, internal carotid artery) in both the left and right carotid arteries. A linear mixed-effects model ...
Experts recommend that clinicians assess motivational factors before initiating care for pediatri... more Experts recommend that clinicians assess motivational factors before initiating care for pediatric obesity. Currently, there are no well-established clinical tools available for assessing motivation in youth with obesity or their families. This represents an important gap in knowledge since motivation-related information may shed light on which patients might fail to complete treatment programs. Our study was designed to evaluate the measurement properties and utility of the Readiness and Motivational Interview for Families (RMI-Family), a structured interview that utilizes a motivational interviewing approach to (i) assess motivational factors in youth and their parents, and (ii) examine the degree to which motivation and motivation-related concordance between youth and parents are related to making changes to lifestyle habits for managing obesity in youth. From 2016 to 2020, this prospective study will include youth with obesity (body mass index [BMI] ≥97th percentile; 13-17 years...
The effects of maternal prepregnancy body mass index (BMI) and gestational weight gain (GWG) on m... more The effects of maternal prepregnancy body mass index (BMI) and gestational weight gain (GWG) on maternal and offspring obesity traits, as well as the maternal and offspring genetic contribution to GWG and postpartum weight retention, were examined. Blood samples from mothers (n = 608) and offspring (n = 541) were genotyped for 83 BMI-associated SNPs and 47 waist-to-hip ratio (WHR)-associated SNPs. Linear regression and mixed-effects regression models were performed to examine clinical epidemiological and genetic associations with unweighted and weighted BMI and WHR genetic risk scores (GRS). Prepregnancy BMI was positively associated with offspring weight and BMI Z-score from birth to 5 years. GWG was positively associated with maternal postpartum weight retention at 1 and 5 years and with offspring weight Z-score from birth to 5 years old. The maternal unweighted BMI GRS was associated with prepregnancy BMI, postpartum weight retention at 5 years, and offspring weight Z-score from ...
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Papers by Katherine Morrison