A mild phenotype associated with KCNQ1 p.V205M mediated long QT syndrome in First Nations children of Northern British Columbia: effect of additional variants and considerations for management.

Introduction: Congenital Long QT Syndrome (LQTS) is common in a First Nations community in Northern British Columbia due to the founder variant KCNQ1 p.V205M. Although well characterized molecularly and clinically in adults, no data have been previously reported on the pediatric population. The phenotype in adults has been shown to be modified by a splice site variant in KCNQ1 (p.L353L). The CPT1A p.P479L metabolic variant, also common in Northern Indigenous populations, is associated with hypoglycemia and infant death. Since hypoglycemia can affect the corrected QT interval (QTc) and may confer risk for seizures (also associated with LQTS), we sought to determine the effect of all three variants on the LQTS phenotype in children within our First Nations cohort. Methods: As part of a larger study assessing those with LQTS and their relatives in a Northern BC First Nation, we assessed those entering the study from birth to age 18 years. We compared the corrected peak QTc and potential cardiac events (syncope/seizures) of 186 children from birth to 18 years, with and without the KCNQ1 (p.V205M and p.L353L) and CPT1A variants, alone and in combination. Linear and logistic regression and student t-tests were applied as appropriate. Results: Only the KCNQ1 p.V205M variant conferred a significant increase in peak QTc 23.8 ms (p < 0.001) above baseline, with females increased by 30.1 ms (p < 0.001) and males by 18.9 ms (p < 0.01). There was no evidence of interaction effects with the other two variants studied. Although the p.V205M variant was not significantly associated with syncope/seizures, the odds of having a seizure/syncope were significantly increased for those homozygous for CPT1A p.P479L compared to homozygous wild type (Odds Ratio [OR]3.0 [95% confidence interval (CI) 1.2-7.7]; p = 0.019). Conclusion: While the KCNQ1 p.V205M variant prolongs the peak QTc, especially in females, the CPT1A p.P479L variant is more strongly associated with loss of consciousness events. These findings suggest that effect of the KCNQ1 p.V205M variant is mild in this cohort, which may have implications for standard management. Our findings also suggest the CPT1A p.P479L variant is a risk factor for seizures and possibly syncope, which may mimic a long QT phenotype.

The multigenerational impact of long QT syndrome: A Gitxsan perspective.

Long QT syndrome (LQTS), a rare cardiac condition that can lead to sudden death, is highly prevalent in First Nations communities of northern British Columbia. In the Gitxsan community of 5500, an estimated 1 in 125 individuals are affected, primarily due to the novel pathogenic variant p.V205M in KCNQ1. Over the past decade, more than 800 Gitxsan individuals received genetic testing and counseling for LQTS through a community-based study. Despite the substantial research characterizing the biological underpinnings of LQTS, there are few studies exploring the lived experiences of families with LQTS, especially those of Indigenous peoples. The goal of this study was to gain a greater understanding of the impact of the genetic confirmation of LQTS in this community, and the impact the condition has on individuals, their families, and the community. A qualitative study was developed in consultation with a local research advisory board and a Talking Circle, a traditional Indigenous format for discussion, was held. Four people who belonged to the same kindred group attended the Talking Circle. This article presents the multigenerational impact that LQTS and genetic diagnosis have through the reflections of one Gitxsan family. LQTS affects identity and family relationships, including those between parents and children, siblings, and even extended family members. Laughter and humor played an important part in coping. The role of family relationships for this Gitxsan family was seen to be critical in managing an LQTS diagnosis. This multigenerational perspective provides key insights into family structure and dynamics which can inform genetic counseling and clinical care. As cultural safety is experienced and therefore defined by the person receiving services, listening to the perspectives and preferences of Indigenous peoples is essential to the delivery of culturally informed care.

Understanding the personal and community impact of long QT syndrome: A perspective from Gitxsan women.

There is a disproportionately high rate of hereditary long QT syndrome (LQTS) in Northern British Columbia First Nations people, largely due to a novel missense variant in KCNQ1 (p.V205M). The variant has been previously described predisposing those affected to syncope, arrhythmia, and sudden death. Although the biological aspects of LQTS have been explored extensively, less research has been done into the impact of living with a genetic variant that predisposes one to sudden death, and no previous studies have provided cultural insights from a First Nations community. The goal of this study was to explore what facilitates and hinders resiliency and coping for those living with LQTS. Participants were invited to partake in their choice of one-to-one interviews, Photovoice, and Talking Circles. This paper presents the findings from the interview portion of the study. Interviews were recorded, transcribed, and analyzed qualitatively using the systematic text condensation method. Ten women shared their personal experiences of living with LQTS through individual interviews. Half of the women had tested positive for the p.V205M variant, and the other half were awaiting results. In general, learning about a LQTS diagnosis was perceived as traumatic, with gradual acceptance that led to coping. The main factors found to facilitate resiliency and coping were positive family relationships, spirituality, and knowledge about LQTS. The main factors found to hinder resiliency and coping were a poor understanding of the biological or clinical aspects of LQTS, conflicting medical advice (especially regarding physical activity) and LQTS not being taken seriously by social contacts and healthcare providers. It appears that learning to live with LQTS is an ongoing process, requiring balance and interconnectedness between all aspects of well-being.

Correction: Hospitalizations due to unintentional transport injuries among Aboriginal population of British Columbia, Canada: Incidence, changes over time and ecological analysis of risk markers.

[This corrects the article DOI: 10.1371/journal.pone.0191384.].

Hospitalizations due to unintentional transport injuries among Aboriginal population of British Columbia, Canada: Incidence, changes over time and ecological analysis of risk markers.

BACKGROUND: Worldwide, Indigenous people have disproportionately higher rates of transport injuries. We examined disparities in injury-related hospitalizations resulting from transport incidents for three population groups in British Columbia (BC): total population, Aboriginal off-reserve, and Aboriginal on-reserve populations. We also examined sociodemographic, geographic and ethnic risk markers for disparities. METHODS: We identified Aboriginal people through BC's universal health care insurance plan insurance premium group and birth and death record notations. We calculated crude incidence rate and Standardized Relative Risk (SRR) of hospitalization for unintentional transport injury, standardized for age, gender and Health Service Delivery Area (HSDA), relative to the total population of BC. We tested hypothesized associations of geographic, socio-economic, and employment-related characteristics of Aboriginal communities with SRR of transport injury by multivariable linear regression. RESULTS: During the period 1991-2010, the SRR for the off-reserve Aboriginal population was 1.77 (95% CI: 1.71 to 1.83); and 2.00 (95% CI: 1.93 to 2.07) among those living on-reserve. Decline in crude rate and SRRs was observed over this period among both the Aboriginal and total populations of BC, but was proportionally greater among the Aboriginal population. The best-fitting multivariable risk marker model was an excellent fit (R2 = 0.912, p<0.001), predicted SRRs very close to observed values, and retained the following terms: urban residence, population per room, proportion of the population with a high school certificate, proportion of the population employed; and multiplicative interactions of Aboriginal ethnicity with population per room and proportion of the population employed. CONCLUSIONS: Disparities in risk of hospitalization due to unintentional transport injury have narrowed. Aboriginal ethnicity modifies the effects of socioeconomic risk factors. Continued improvement of socioeconomic conditions and implementation of culturally relevant injury prevention interventions are needed.

Iatrogenic Injury among the Aboriginal and Total Populations of British Columbia, Canada, 1991-2010: Inequities Associated with Ethnicity and Socioeconomic Status.

PURPOSE: Measure population health impact, and socioeconomic, geographic, and ethnic predictors of iatrogenic injury. METHODS: Within three groups (total population, Aboriginal off-reserve, and Aboriginal on-reserve) in each of 16 Health Service Delivery Areas (HSDAs) of British Columbia, Canada we calculated crude incidence and Standardized Relative Risk (SRR) of hospitalization for iatrogenic injury. We tested hypothesized associations between HSDA census characteristics and SRR, by multivariable regression. RESULTS: Among hospitalizations due to any injury, 22.2% were iatrogenic. Crude rate of iatrogenic injury hospitalization was 20.4 per 10,000 person-years. Aboriginal rate was 24.4 per 10,000 and SRR was 1.57 (1.76 among females, 1.38 among males). Non-metropolitan HSDAs had higher SRRs. The best-fitting regression model was an excellent fit (R=0.836, p<.001) and included education, income, house needs major repairs, population per room, and Aboriginal ethnicity. CONCLUSIONS: Iatrogenic injury has significant population health impact. Aboriginal people, especially females, have higher risk. Ethnicity and socioeconomic factors explain regional disparities.

Intentional injury among the indigenous and total populations in British Columbia, Canada: trends over time and ecological analyses of risk.

BACKGROUND: Our objective was to explore intentional injury disparity between Indigenous populations and the total population in the province of British Columbia (BC), Canada. We focus on hospitalizations, including both self-inflicted injuries and injuries inflicted by others. METHODS: We used data from BC's universal health care insurance plan, 1991 to 2010, linked to Vital Statistics databases. Indigenous people were identified through the insurance premium group, and birth and death records. Place of residence was identified through postal code. We calculated crude hospitalization incidence rates and the Standardized Relative Risk (SRR) of hospitalization, standardized by gender, 5-year age group, and Health Service Delivery Area (HSDA). With HSDA populations as the units of observation, linear regression was used to test hypothesized associations of Indigenous ethnicity, geographic, and socio-economic characteristics with SRR of injury. RESULTS: During the period 1991-2010, the crude rate of hospitalization for intentional injuries was 8.4 per 10,000 person-years (95% confidence interval (CI): 8.3 to 8.5) for the total BC population, compared to 45.3 per 10,000 (95% CI: 44.5 to 46.1) for the Indigenous population. For both populations, risk declined over the period for injuries self-inflicted and inflicted by others. The linear regression model predicts that the off-reserve Indigenous population will have SRR of intentional injury 3.98 greater, and the on-reserve Indigenous population 4.17, greater than the total population. The final model was an excellent fit (R2 = 0.912, F = 177.632, p < 0.001), and found that three variables - occupational risk, high school diploma, and university degree - each provide independent effects when interacting multiplicatively with Indigenous ethnicity. CONCLUSIONS: The observation of substantially declining rates of intentional injury for both the Indigenous and total BC populations is off-set by the high disparity in risk between the two populations, which will likely continue until Canada reduces disparity with respect to discriminatory practices, and physical, social, and economic conditions.

Risk of Hospitalization Due to Unintentional Fall Injury in British Columbia, Canada, 1999-2008: Ecological Associations with Socioeconomic Status, Geographic Place, and Aboriginal Ethnicity.

BACKGROUND: Aboriginal people in British Columbia (BC), especially those residing on Indian reserves, have higher risk of unintentional fall injury than the general population. We test the hypothesis that the disparities are attributable to a combination of socioeconomic status, geographic place, and Aboriginal ethnicity. METHODS: Within each of 16 Health Service Delivery Areas in BC, we identified three population groups: total population, Aboriginal off-reserve, and Aboriginal on-reserve. We calculated age and gender-standardized relative risks (SRR) of hospitalization due to unintentional fall injury (relative to the total population of BC), during time periods 1999-2003 and 2004-2008, and we obtained custom data from the 2001 and 2006 censuses (long form), describing income, education, employment, housing, proportions of urban and rural dwellers, and prevalence of Aboriginal ethnicity. We studied association of census characteristics with SRR of fall injury, by multivariable linear regression. RESULTS: The best-fitting model was an excellent fit (R 2 = 0.854, p < 0.001) and predicted SRRs very close to observed values for the total, Aboriginal off-reserve, and Aboriginal on-reserve populations of BC. After stepwise regression, the following terms remained: population per room, urban residence, labor force participation, income per capita, and multiplicative interactions of Aboriginal ethnicity with population per room and labor force participation. CONCLUSIONS: The disparities are predictable by the hypothesized risk markers. Aboriginal ethnicity is not an independent risk marker: it modifies the effects of socioeconomic factors. Closing the gap in fall injury risk between the general and Aboriginal populations is likely achievable by closing the gaps in socioeconomic conditions.

Injuries to Aboriginal populations living on- and off-reserve in metropolitan and non-metropolitan areas in British Columbia, Canada: Incidence and trends, 1986-2010.

BACKGROUND: Disparities in injury rates between Aboriginal and non-Aboriginal populations in British Columbia (BC) are well established. Information regarding the influence of residence on disparities is scarce. We sought to fill these gaps by examining hospitalization rates for all injuries, unintentional injuries and intentional injuries across 24 years among i) Aboriginal and total populations; ii) populations living in metropolitan and non-metropolitan areas; and iii) Aboriginal populations living on- and off-reserve. METHODS: We used data spanning 1986 through 2010 from BC's universal health care insurance plan, linked to vital statistics databases. Aboriginal people were identified by insurance premium group and birth and death record notations, and their residence was determined by postal code. "On-reserve" residence was established by postal code areas associated with an Indian reserve or settlement. Health Service Delivery Areas (HSDAs) were classified as "metropolitan" if they contained a population of at least 100,000 with a density of 400 or more people per square kilometre. We calculated the crude hospitalization incidence rate and the Standardized Relative Risk (SRR) of hospitalization due to injury standardizing by gender, 5-year age group, and HSDA. We assessed cumulative change in SRR over time as the relative change between the first and last years of the observation period. RESULTS: Aboriginal metropolitan populations living off-reserve had the lowest SRR of injury (2.0), but this was 2.3 times greater than the general British Columbia metropolitan population (0.86). For intentional injuries, Aboriginal populations living on-reserve in non-metropolitan areas were at 5.9 times greater risk than the total BC population. In general, the largest injury disparities were evident for Aboriginal non-metropolitan populations living on-reserve (SRR 3.0); 2.5 times greater than the general BC non-metropolitan population (1.2). Time trends indicated decreasing disparities, with Aboriginal non-metropolitan populations experiencing the largest declines in injury rates. CONCLUSIONS: Metropolitan/non-metropolitan residence appears to be a more important predictor than on/off-reserve residence for all injuries and unintentional injuries, and the relationship was even more pronounced for intentional injuries. The persistent disparities highlight the need for culturally sensitive and geographically relevant injury prevention approaches.

Primary care visits due to injuries among the Aboriginal off-reserve population of British Columbia, Canada, 1991-2010.

BACKGROUND: Aboriginal people in British Columbia (BC) have higher injury incidence than the general population. This report describes variability in visits to primary care due to injury, among injury categories, time periods, geographies, and demographic groups. METHODS: We used BC's universal health care insurance plan as a population registry, linked to practitioner payment and vital statistics databases. We identified Aboriginal people by insurance premium group and birth and death record notations. Within that population we identified those residing off-reserve according to postal code. We calculated crude incidence and Standardized Relative Risk (SRR) of primary care visit due to injury, standardized for age, gender and Health Service Delivery Area (HSDA), relative to the total population of BC. RESULTS: During 1991 through 2010, the crude rate of primary care visit due to injury in BC was 3172 per 10,000 person-years. The Aboriginal off-reserve rate was 4291 per 10,000 and SRR was 1.41 (95 % confidence interval: 1.41 to 1.42). Northern and non-metropolitan HSDAs had higher SRRs, within both total BC and Aboriginal off-reserve populations. In every age and gender category, the HSDA-standardized SRR was higher among the Aboriginal off-reserve than among the total population. For all injuries combined, and for the categories of trauma, poisoning, and burn, between 1991 and 2010, crude rates and SRRs declined substantially, but proportionally more rapidly among the Aboriginal off-reserve population, so the gap between the Aboriginal off-reserve and total populations is narrowing, particularly among metropolitan residents. CONCLUSIONS: These findings corroborate our previous reports regarding hospitalizations due to injury, suggesting that our observations reflect real disparities and changes in the underlying incidence of injury, and are not merely artefacts related to health care utilization.

Suicide Among Inuit: Results From a Large, Epidemiologically Representative Follow-Back Study in Nunavut.

OBJECTIVE: The Inuit population in Canada's North has suffered from high rates of death by suicide. We report on the first large-scale, controlled, epidemiologically representative study of deaths by suicide in an Indigenous population, which investigates risk factors for suicide among all Inuit across Nunavut who died by suicide during a 4-year period. METHODS: We identified all suicides by Inuit (n = 120) that occurred between January 1, 2003, and December 31, 2006, in Nunavut. For each subject, we selected a community-matched control subject. We used proxy-based procedures and conducted structured interviews with informants to obtain life histories, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I and II diagnoses, and measures of impulsive and (or) aggressive traits. RESULTS: Compared with control subjects, subjects who died by suicide were more likely to have experienced childhood abuse (OR 2.38; 95% CI 1.39 to 4.08), have family histories of major depressive disorder (P = 0.002) and suicide completion (P = 0.02), and have been affected by major depressive disorder (OR 13.00; 95% CI 6.20 to 27.25), alcohol dependence (OR 2.90; 95% CI 1.59 to 5.24), or cannabis dependence (OR 3.96; 95% CI 2.29 to 6.8) in the last 6 months. In addition, subjects who died by suicide were more likely to have been affected with cluster B personality disorders (OR 10.18; 95% CI 3.34 to 30.80) and had higher scores of impulsive and aggressive traits (P < 0.001). CONCLUSIONS: At the individual level, clinical risk factors for suicide among Inuit are similar to those observed in studies with the general population, and indicate a need for improved access to mental health services. The high rate of mental health problems among control subjects suggests the need for population-level mental health promotion.

Injury hospitalizations due to unintentional falls among the Aboriginal population of British Columbia, Canada: incidence, changes over time, and ecological analysis of risk markers, 1991-2010.

BACKGROUND: Aboriginal people in British Columbia (BC) have higher injury incidence than the general population. Our project describes variability among injury categories, time periods, and geographic, demographic and socio-economic groups. This report focuses on unintentional falls. METHODS: We used BC's universal health care insurance plan as a population registry, linked to hospital separation and vital statistics databases. We identified Aboriginal people by insurance premium group and birth and death record notations. We identified residents of specific Aboriginal communities by postal code. We calculated crude incidence and Standardized Relative Risk (SRR) of hospitalization for unintentional fall injury, standardized for age, gender and Health Service Delivery Area (HSDA), relative to the total population of BC. We tested hypothesized associations of geographic, socio-economic, and employment-related characteristics with community SRR of injury by linear regression. RESULTS: During 1991 through 2010, the crude rate of hospitalization for unintentional fall injury in BC was 33.6 per 10,000 person-years. The Aboriginal rate was 49.9 per 10,000 and SRR was 1.89 (95% confidence interval 1.85-1.94). Among those living on reserves SRR was 2.00 (95% CI 1.93-2.07). Northern and non-urban HSDAs had higher SRRs, within both total and Aboriginal populations. In every age and gender category, the HSDA-standardized SRR was higher among the Aboriginal than among the total population. Between 1991 and 2010, crude rates and SRRs declined substantially, but proportionally more among the Aboriginal population, so the gap between the Aboriginal and total population is narrowing, particularly among females and older adults. These community characteristics were associated with higher risk: lower income, lower educational level, worse housing conditions, and more hazardous types of employment. CONCLUSIONS: Over the years, as socio-economic conditions improve, risk of hospitalization due to unintentional fall injury has declined among the Aboriginal population. Women and older adults have benefited more.

Injury risk in British Columbia, Canada, 1986 to 2009: are Aboriginal children and youth over-represented?

BACKGROUND: Children and youth worldwide are at high risk of injury resulting in morbidity, disability or mortality. Disparities in risk exist between and within countries, and by sex and ethnicity. Our aim is to contribute data on disparities of injury rates for Aboriginal children and youth compared with those of the general population in British Columbia (BC), Canada, by examining risks for the two populations, utilizing provincial administrative data over a 24-year period. METHODS: Hospital discharge records from the provincial health care database for children and youth were used to identify injury for the years 1986 to 2009. Within the total BC population, the Aboriginal population was identified. Crude rates and standardized relative risks (SRR) of hospitalization were calculated, by year and category of injury type and external cause, and compared to the total BC population for males and females under age 25 years. RESULTS: Over the 24-year period, substantive decreases were found in hospitalization injury risks for children and youth in both Aboriginal and total populations, for both sexes, and for most categories and types of injuries. Risk in overall injury dropped by 69% for the Aboriginal population and by 66% for the total BC population, yet in every year, the Aboriginal population had a higher risk than the total BC population. There were over 70% declines in risks among females of intentionally inflicted injury by another, among both the Aboriginal and total BC populations. Risk of injury caused by transport vehicles has decreased by an overwhelming 83% and 72% for the Aboriginal male population and for the total BC male population, respectively. CONCLUSIONS: The over 70% declines in risks for females of intentionally inflicted injury by another, among both the Aboriginal and total BC populations is excellent news. Risk of injury caused by transport vehicles for males decreased overwhelmingly for both populations. Disparities in rates between the Aboriginal population and total BC population remain because of similarity in the proportional reductions among the two populations. Since the Aboriginal population started at a much higher risk, in absolute terms, the gap between the two populations is shrinking.

The RISC research project: injury in First Nations communities in British Columbia, Canada.

BACKGROUND: The project, Injury in British Columbia's Aboriginal Communities: Building Capacity while Developing Knowledge, funded by the Canadian Institutes of Health Research (CIHR), aims to expand knowledge on injury rates among First Nations communities in British Columbia (BC), Canada. OBJECTIVE: The purpose is to improve understanding of community differences and to identify community-level risk and protective factors. Generally, injury incidence rates in the Aboriginal population in Canada greatly exceed those found in the non-Aboriginal population; however, variability exists between Aboriginal communities, which have important implications for prevention. DESIGN: This study uses administrative records of deaths, hospitalizations, ambulatory care episodes, and workers' compensation claims due to injuries to identify communities that have been especially successful in maintaining low rates of injury. RESULTS: The analysis of risk and protective factors extends the work of Chandler and Lalonde who observed that community efforts to preserve and promote Aboriginal culture and to maintain local control over community life are strongly associated with lower suicide rates. CONCLUSION: The discussion on psychological and cultural considerations on healing and reducing the rates of injury expands the work of McCormick on substance use in Aboriginal communities.