Younger but sicker? Cohort trends in disease accumulation among middle-aged and older adults in Scotland using health-linked data from the Scottish Longitudinal Study.

BACKGROUND: In the United Kingdom, rising prevalence of multimorbidity-the co-occurrence of two or more chronic conditions- is coinciding with stagnation in life expectancy. We investigate patterns of disease accumulation and how they vary by birth cohort, social and environmental inequalities in Scotland, a country which has long suffered from excess mortality and poorer health outcomes relative to its neighbours. METHODS: Using a dataset which links census data from 1991, 2001 and 2011 to disease registers and hospitalization data, we follow cohorts of adults aged 30-69 years for 18 years. We model physical and mental disease accumulation using linear mixed-effects models. RESULTS: Recent cohorts experience higher levels of chronic disease accumulation compared to their predecessors at the same ages. Moreover, in more recently born cohorts we observe socioeconomic status disparities emerging earlier in the life course, which widen over time and with every successive cohort. Patterns of chronic conditions are also changing, and the most common diseases suffered by later born cohorts are cancer, hypertension, asthma, drug and alcohol problems and depression. CONCLUSION: We recommend policies which target prevention of chronic disease in working age adults, considering how and why certain conditions are becoming more prevalent across time and space.

SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy.

Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (P = 7.5 × 10-9) and 10p11.21 (P = 3.6 × 10-8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10-3). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (P = 0.0005) including NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila polypeptide with the highest homology to SLCO5A1, causes over-reactive startling behaviour (P = 8.7 × 10-3) and increased seizure-like events (P = 6.8 × 10-7). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10-3). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.

Bacterial etiology of urinary tract infections in patients treated at Kenyan health facilities and their resistance towards commonly used antibiotics.

BACKGROUND: Evidence-based empirical antibiotic prescribing requires knowledge of local antimicrobial resistance patterns. The spectrum of pathogens and their susceptibility strongly influences guidelines for empirical therapies for urinary tract infections (UTI) management. OBJECTIVE: This study aimed to determine the prevalence of UTI causative bacteria and their corresponding antibiotic resistance profiles in three counties of Kenya. Such data could be used to determine the optimal empirical therapy. METHODS: In this cross-sectional study, urine samples were collected from patients who presented with symptoms suggestive of UTI in the following healthcare facilities; Kenyatta National Hospital, Kiambu Hospital, Mbagathi, Makueni, Nanyuki, Centre for Microbiology Research, and Mukuru Health Centres. Urine cultures were done on Cystine Lactose Electrolyte Deficient (CLED) to isolate UTI bacterial etiologies, while antibiotic sensitivity testing was done using the Kirby-Bauer disk diffusion using CLSI guidelines and interpretive criteria. RESULTS: A total of 1,027(54%) uropathogens were isolated from the urine samples of 1898 participants. Staphylococcus spp. and Escherichia coli were the main uropathogens at 37.6% and 30.9%, respectively. The percentage resistance to commonly used drugs for the treatment of UTI were as follows: trimethoprim (64%), sulfamethoxazole (57%), nalidixic acid(57%), ciprofloxacin (27%), amoxicillin-clavulanic acid (5%), and nitrofurantoin (9%) and cefixime (9%). Resistance rates to broad-spectrum antimicrobials, such as ceftazidime, gentamicin, and ceftriaxone, were 15%, 14%, and 11%, respectively. Additionally, the proportion of Multidrug-resistant (MDR) bacteria was 66%. CONCLUSION: High resistance rates toward fluoroquinolones, sulfamethoxazole, and trimethoprim were reported. These antibiotics are commonly used drugs as they are inexpensive and readily available. Based on these findings, more robust standardised surveillance is needed to confirm the patterns observed while recognising the potential impact of sampling biases on observed resistance rates.

Rapid chloride and bicarbonate determination by capillary electrophoresis for confirmatory testing of cystic fibrosis infants with volume-limited sweat specimens.

Objectives Cystic fibrosis (CF) is a debilitating genetic disorder that benefits from early detection. CF diagnosis relies on measuring elevated sweat chloride that is difficult in neonates with low sweat rates. We introduce a new method for sweat chloride determination from volume-limited specimens, and explore the potential utility of sweat bicarbonate in neonatal CF screening. Methods A rapid assay (< 5 min) was developed to analyze chloride and bicarbonate using capillary electrophoresis with indirect UV detection (CE-iUV). Pilocarpine-stimulated sweat samples from screen-positive CF infants were collected at two hospital sites, including confirmed CF (n = 12), CF screen-positive inconclusive diagnosis (n = 4), and unaffected non-CF cases (n = 37). All sweat chloride samples were analyzed by a coulometric titrator and CE-iUV, and the viability to measure acid-labile bicarbonate was also evaluated. Results Stability studies revealed that bicarbonate can be reliably assessed in sweat if acidification and heating were avoided. Method validation demonstrated that sweat chloride and bicarbonate were quantified with acceptable accuracy (recovery of 102%), precision (CV = 3.7%) and detection limits (∼ 0.1 mM). An inter-laboratory comparison confirmed a mean bias of 6.5% (n = 53) for sweat chloride determination by CE-iUV relative to a commercial chloridometer. However, sweat bicarbonate did not discriminate between CF and non-CF infants (AUC = 0.623, p = 0.215) unlike chloride (AUC = 1.00, p = 3.00 × 10-7). Conclusions CE-iUV offers a robust method for sweat chloride testing from presumptive CF infants that may reduce testing failure rates. However, sweat bicarbonate does not have clinical value in newborn CF diagnosis.

High-quality read-based phasing of cystic fibrosis cohort informs genetic understanding of disease modification.

Phasing of heterozygous alleles is critical for interpretation of cis-effects of disease-relevant variation. We sequenced 477 individuals with cystic fibrosis (CF) using linked-read sequencing, which display an average phase block N50 of 4.39 Mb. We use these samples to construct a graph representation of CFTR haplotypes, demonstrating its utility for understanding complex CF alleles. These are visualized in a Web app, CFTbaRcodes, that enables interactive exploration of CFTR haplotypes present in this cohort. We perform fine-mapping and phasing of the chr7q35 trypsinogen locus associated with CF meconium ileus, an intestinal obstruction at birth associated with more severe CF outcomes and pancreatic disease. A 20-kb deletion polymorphism and a PRSS2 missense variant p.Thr8Ile (rs62473563) are shown to independently contribute to meconium ileus risk (p = 0.0028, p = 0.011, respectively) and are PRSS2 pancreas eQTLs (p = 9.5 × 10-7 and p = 1.4 × 10-4, respectively), suggesting the mechanism by which these polymorphisms contribute to CF. The phase information from linked reads provides a putative causal explanation for variation at a CF-relevant locus, which also has implications for the genetic basis of non-CF pancreatitis, to which this locus has been reported to contribute.

Treatment of missing data in Bayesian network structure learning: an application to linked biomedical and social survey data.

BACKGROUND: Availability of linked biomedical and social science data has risen dramatically in past decades, facilitating holistic and systems-based analyses. Among these, Bayesian networks have great potential to tackle complex interdisciplinary problems, because they can easily model inter-relations between variables. They work by encoding conditional independence relationships discovered via advanced inference algorithms. One challenge is dealing with missing data, ubiquitous in survey or biomedical datasets. Missing data is rarely addressed in an advanced way in Bayesian networks; the most common approach is to discard all samples containing missing measurements. This can lead to biased estimates. Here, we examine how Bayesian network structure learning can incorporate missing data. METHODS: We use a simulation approach to compare a commonly used method in frequentist statistics, multiple imputation by chained equations (MICE), with one specific for Bayesian network learning, structural expectation-maximization (SEM). We simulate multiple incomplete categorical (discrete) data sets with different missingness mechanisms, variable numbers, data amount, and missingness proportions. We evaluate performance of MICE and SEM in capturing network structure. We then apply SEM combined with community analysis to a real-world dataset of linked biomedical and social data to investigate associations between socio-demographic factors and multiple chronic conditions in the US elderly population. RESULTS: We find that applying either method (MICE or SEM) provides better structure recovery than doing nothing, and SEM in general outperforms MICE. This finding is robust across missingness mechanisms, variable numbers, data amount and missingness proportions. We also find that imputed data from SEM is more accurate than from MICE. Our real-world application recovers known inter-relationships among socio-demographic factors and common multimorbidities. This network analysis also highlights potential areas of investigation, such as links between cancer and cognitive impairment and disconnect between self-assessed memory decline and standard cognitive impairment measurement. CONCLUSION: Our simulation results suggest taking advantage of the additional information provided by network structure during SEM improves the performance of Bayesian networks; this might be especially useful for social science and other interdisciplinary analyses. Our case study show that comorbidities of different diseases interact with each other and are closely associated with socio-demographic factors.

Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease.

Over 400 variants in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) are CF-causing. CFTR modulators target variants to improve lung function, but marked variability in response exists and current therapies do not address all CF-causing variants highlighting unmet needs. Alternative epithelial ion channel/transporters such as SLC26A9 could compensate for CFTR dysfunction, providing therapeutic targets that may benefit all individuals with CF. We investigate the relationship between rs7512462, a marker of SLC26A9 activity, and lung function pre- and post-treatment with CFTR modulators in Canadian and US CF cohorts, in the general population, and in those with chronic obstructive pulmonary disease (COPD). Rs7512462 CC genotype is associated with greater lung function in CF individuals with minimal function variants (for which there are currently no approved therapies; p = 0.008); and for gating (p = 0.033) and p.Phe508del/ p.Phe508del (p = 0.006) genotypes upon treatment with CFTR modulators. In parallel, human nasal epithelia with CC and p.Phe508del/p.Phe508del after Ussing chamber analysis of a combination of approved and experimental modulator treatments show greater CFTR function (p = 0.0022). Beyond CF, rs7512462 is associated with peak expiratory flow in a meta-analysis of the UK Biobank and Spirometa Consortium (p = 2.74 × 10-44) and provides p = 0.0891 in an analysis of COPD case-control status in the UK Biobank defined by spirometry. These findings support SLC26A9 as a therapeutic target to improve lung function for all people with CF and in individuals with other obstructive lung diseases.

Outcomes of Cystic Fibrosis Screening-Positive Infants With Inconclusive Diagnosis at School Age.

BACKGROUND AND OBJECTIVES: Cystic fibrosis (CF) screen-positive infants with an inconclusive diagnosis (CFSPID) are infants in whom sweat testing and genetic analysis does not resolve a CF diagnosis. Lack of knowledge about the health outcome of these children who require clinical follow-up challenges effective consultation. Early predictive biomarkers to delineate the CF risk would allow a more targeted approach to these children. METHODS: Prospective, longitudinal, multicenter, Canada-wide cohort study of CF positive-screened newborns with 1 to 2 cystic fibrosis transmembrane conductance regulator gene variants, of which at least 1 is not known to be CF-causing and/or a sweat chloride between 30 and 59 mmol/L. These were monitored for conversion to a CF diagnosis, pulmonary, and nutritional outcomes. RESULTS: The mean observation period was 7.7 (95% confidence interval 7.1 to 8.4) years. A CF diagnosis was established for 24 of the 115 children with CFSPID (21%) either because of reinterpretation of the cystic fibrosis transmembrane conductance regulator genotype or because of increase in sweat chloride concentration ≥60 mmol/L. An initial sweat chloride of ≥40 mmol/l predicted conversion to CF on the basis of sweat testing. The 91 remaining children with CFSPID were pancreatic sufficient and showed normal growth until school age. Pulmonary function as well as lung clearance index in a subgroup of children with CFSPID were similar to that of healthy controls. CONCLUSIONS: Children with CFSPID have good nutritional and pulmonary outcomes at school age, but rates of reclassifying the diagnosis are high. The initial sweat chloride test can be used as a biomarker to predict the risk for CF in CFSPID.

Cystic fibrosis-related diabetes onset can be predicted using biomarkers measured at birth.

PURPOSE: Cystic fibrosis (CF), caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR), affects multiple organs including the exocrine pancreas, which is a causal contributor to cystic fibrosis-related diabetes (CFRD). Untreated CFRD causes increased CF-related mortality whereas early detection can improve outcomes. METHODS: Using genetic and easily accessible clinical measures available at birth, we constructed a CFRD prediction model using the Canadian CF Gene Modifier Study (CGS; n = 1,958) and validated it in the French CF Gene Modifier Study (FGMS; n = 1,003). We investigated genetic variants shown to associate with CF disease severity across multiple organs in genome-wide association studies. RESULTS: The strongest predictors included sex, CFTR severity score, and several genetic variants including one annotated to PRSS1, which encodes cationic trypsinogen. The final model defined in the CGS shows excellent agreement when validated on the FGMS, and the risk classifier shows slightly better performance at predicting CFRD risk later in life in both studies. CONCLUSION: We demonstrated clinical utility by comparing CFRD prevalence rates between the top 10% of individuals with the highest risk and the bottom 10% with the lowest risk. A web-based application was developed to provide practitioners with patient-specific CFRD risk to guide CFRD monitoring and treatment.

Prodrugs of PKC modulators show enhanced HIV latency reversal and an expanded therapeutic window.

AIDS is a pandemic disease caused by HIV that affects 37 million people worldwide. Current antiretroviral therapy slows disease progression but does not eliminate latently infected cells, which resupply active virus, thus necessitating lifelong treatment with associated compliance, cost, and chemoexposure issues. Latency-reversing agents (LRAs) activate these cells, allowing for their potential clearance, thus presenting a strategy to eradicate the infection. Protein kinase C (PKC) modulators-including prostratin, ingenol esters, bryostatin, and their analogs-are potent LRAs in various stages of development for several clinical indications. While LRAs are promising, a major challenge associated with their clinical use is sustaining therapeutically meaningful levels of the active agent while minimizing side effects. Here we describe a strategy to address this problem based on LRA prodrugs, designed for controllable release of the active LRA after a single injection. As intended, these prodrugs exhibit comparable or superior in vitro activity relative to the parent compounds. Selected compounds induced higher in vivo expression of CD69, an activation biomarker, and, by releasing free agent over time, significantly improved tolerability when compared to the parent LRAs. More generally, selected prodrugs of PKC modulators avoid the bolus toxicities of the parent drug and exhibit greater efficacy and expanded tolerability, thereby addressing a longstanding objective for many clinical applications.

Immunoreactive trypsinogen levels in newborn screened infants with an inconclusive diagnosis of cystic fibrosis.

BACKGROUND: Newborn screening (NBS) for cystic fibrosis (CF) not only identifies infants with a diagnosis of CF, but also those with an uncertain diagnosis of cystic fibrosis (CF), i.e. CF transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS) or CF screen positive inconclusive diagnosis (CFSPID). These infants have an uncertain long-term outcome and it is currently unclear around time of diagnosis, which infants are at higher risk of later fulfilling a CF diagnosis. In this study, we hypothesised that immunoreactive trypsinogen (IRT) levels, used in NBS as a marker of pancreatic disease and function, may reflect the degree of CFTR dysfunction in each individual and therefore would help to identify those with CRMS/CSPID who are later at risk for meeting the criteria of CF. METHODS: In this longitudinal, prospective study, infants with CRMS/CFSPID and CF were recruited and followed in 9 CF clinics (Canada and Italy). We compared NBS IRT levels between CF and CRMS/CFSPID, and between children with CRMS/CFSPID→CF and CRMS/CFSPID→CRMS/CFSPID during the period of June 2007 to April 2016. RESULTS: Ninety eight CRMS/CFSPID and 120 CF subjects were enrolled. During the study period, 14 (14.3%) CRMS/CFSPID subjects fulfilled the diagnostic criteria for CF (CRMS/CFSPID→CF), while the diagnosis remained uncertain (CRMS/CFSPID→ CRMS/CFSPID) in 84 (85.7%) subjects. Significantly higher NBS IRT concentrations (ng/ml) were present in CF than CRMS/CFPSID (median (interquartile range): 143.8 (99.8-206.2) vs. 75.0 (61.0-105.9); P < 0.0001). Infants with CRMS/CFSPID→CF (n = 14) had significantly higher NBS IRT concentrations (ng/ml) than CRMS/CFSPID→ CRMS/CFSPID (n = 83) (median (interquartile range): 108.9 (72.3-126.8) vs. 73.7(60.0-96.0); P = 0.02). CONCLUSIONS: Amongst infants who tested positive on NBS for CF, there is a gradation of elevated NBS IRT concentrations. Infants with CF have higher NBS IRT levels than CRMS/CFPSID, and higher NBS IRT concentrations were present in infants with CRMS/CFSPID→CF than CRMS/CFSPID→ CRMS/CFSPID. NBS IRT concentrations, in concert with other factors, may have the potential to predict the likelihood of CF amongst infants with CRMS/CFSPID.

Genetic association and transcriptome integration identify contributing genes and tissues at cystic fibrosis modifier loci.

Cystic Fibrosis (CF) exhibits morbidity in several organs, including progressive lung disease in all patients and intestinal obstruction at birth (meconium ileus) in ~15%. Individuals with the same causal CFTR mutations show variable disease presentation which is partly attributed to modifier genes. With >6,500 participants from the International CF Gene Modifier Consortium, genome-wide association investigation identified a new modifier locus for meconium ileus encompassing ATP12A on chromosome 13 (min p = 3.83x10(-10)); replicated loci encompassing SLC6A14 on chromosome X and SLC26A9 on chromosome 1, (min p<2.2x10(-16), 2.81x10(-11), respectively); and replicated a suggestive locus on chromosome 7 near PRSS1 (min p = 2.55x10(-7)). PRSS1 is exclusively expressed in the exocrine pancreas and was previously associated with non-CF pancreatitis with functional characterization demonstrating impact on PRSS1 gene expression. We thus asked whether the other meconium ileus modifier loci impact gene expression and in which organ. We developed and applied a colocalization framework called the Simple Sum (SS) that integrates regulatory and genetic association information, and also contrasts colocalization evidence across tissues or genes. The associated modifier loci colocalized with expression quantitative trait loci (eQTLs) for ATP12A (p = 3.35x10(-8)), SLC6A14 (p = 1.12x10(-10)) and SLC26A9 (p = 4.48x10(-5)) in the pancreas, even though meconium ileus manifests in the intestine. The meconium ileus susceptibility locus on chromosome X appeared shifted in location from a previously identified locus for CF lung disease severity. Using the SS we integrated the lung disease association locus with eQTLs from nasal epithelia of 63 CF participants and demonstrated evidence of colocalization with airway-specific regulation of SLC6A14 (p = 2.3x10(-4)). Cystic Fibrosis is realizing the promise of personalized medicine, and identification of the contributing organ and understanding of tissue specificity for a gene modifier is essential for the next phase of personalizing therapeutic strategies.

Phenotypic spectrum of patients with cystic fibrosis and cystic fibrosis-related disease carrying p.Arg117His.

BACKGROUND: The "mild" gene variant, p.Arg117His in cystic fibrosis (CF) results in highly variable phenotypes ranging from male infertility to severe lung disease. Due to current interest to include this group in CFTR-targeted therapies, this study aims to describe the disease spectrum. METHODS: Retrospective study of Toronto CF and CFTR-related p.Arg117His patients. Longitudinally captured clinical data were compared between patients with 5T/7T-variants and those with a CF or CFTR-related diagnosis. Comparison was made between p.Arg117His adults and infants identified through CF newborn screening (NBS). RESULTS: Twenty of fifty patients carried the 5T variant, all with a diagnosis of CF (p.Arg117His-5TCF), and 30/50 carried 7T, 7 diagnosed with CF (p.Arg117His-7TCF) and 23 with a CFTR-related disorder (p.Arg117His-7TCFTR). For those with chest HRCT results available, 75% p.Arg117His-5TCF, 33% p.Arg117His-7TCF and 27% p.Arg117His-7TCFTR patients had bronchiectasis. Further, 79% p.Arg117His-5T, 29% p.Arg117His-7TCF and 13% p.Arg117His-7TCFTR had abnormal lung function. Of those, 80% grew CF-related pathogens on respiratory culture. Interestingly, the mean maximum sweat chloride and the percentage of patients growing CF-related bacterial pathogens were identical in p.Arg117His-7 TCFTR adults and p.Arg117His infants. CONCLUSIONS: Generally, p.Arg117His-5T patients had more severe CF disease. However, a subset of p.Arg117His-7 T patients demonstrated equally severe disease, thus warranting clinical monitoring of all p.Arg117His patients including p.Arg117His infants identified via NBS.

Improving imputation in disease-relevant regions: lessons from cystic fibrosis.

Does genotype imputation with public reference panels identify variants contributing to disease? Genotype imputation using the 1000 Genomes Project (1KG; 2504 individuals) displayed poor coverage at the causal cystic fibrosis (CF) transmembrane conductance regulator (CFTR) locus for the International CF Gene Modifier Consortium. Imputation with the larger Haplotype Reference Consortium (HRC; 32,470 individuals) displayed improved coverage but low sensitivity of variants clinically relevant for CF. A hybrid reference that combined whole genome sequencing (WGS) from 101 CF individuals with the 1KG imputed a greater number of single-nucleotide variants (SNVs) that would be analyzed in a genetic association study (r2 ≥ 0.3 and MAF ≥ 0.5%) than imputation with the HRC, while the HRC excelled in the lower frequency spectrum. Using the 1KG or HRC as reference panels missed the most common CF-causing variants or displayed low imputation accuracy. Designs that incorporate population-specific WGS can improve imputation accuracy at disease-specific loci, while imputation using public data sets can omit disease-relevant genotypes.

The Sweat Metabolome of Screen-Positive Cystic Fibrosis Infants: Revealing Mechanisms beyond Impaired Chloride Transport.

The sweat chloride test remains the gold standard for confirmatory diagnosis of cystic fibrosis (CF) in support of universal newborn screening programs. However, it provides ambiguous results for intermediate sweat chloride cases while not reflecting disease progression when classifying the complex CF disease spectrum given the pleiotropic effects of gene modifiers and environment. Herein we report the first characterization of the sweat metabolome from screen-positive CF infants and identify metabolites associated with disease status that complement sweat chloride testing. Pilocarpine-stimulated sweat specimens were collected independently from two CF clinics, including 50 unaffected infants (e.g., carriers) and 18 confirmed CF cases. Nontargeted metabolite profiling was performed using multisegment injection-capillary electrophoresis-mass spectrometry as a high throughput platform for analysis of polar/ionic metabolites in volume-restricted sweat samples. Amino acids, organic acids, amino acid derivatives, dipeptides, purine derivatives, and unknown exogenous compounds were identified in sweat when using high resolution tandem mass spectrometry, including metabolites associated with affected yet asymptomatic CF infants, such as asparagine and glutamine. Unexpectedly, a metabolite of pilocarpine, used to stimulate sweat secretion, pilocarpic acid, and a plasticizer metabolite from environmental exposure, mono(2-ethylhexyl)phthalic acid, were secreted in the sweat of CF infants at significantly lower concentrations relative to unaffected CF screen-positive controls. These results indicated a deficiency in human paraoxonase, an enzyme unrelated to mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) and impaired chloride transport, which is a nonspecific arylesterase/lactonase known to mediate inflammation, bacterial biofilm formation, and recurrent lung infections in affected CF children later in life. This work sheds new light into the underlying mechanisms of CF pathophysiology as required for new advances in precision medicine of orphan diseases that benefit from early detection and intervention, including new molecular targets for therapeutic intervention.

Psychosocial Response to Uncertain Newborn Screening Results for Cystic Fibrosis.

OBJECTIVE: To explore the psychosocial implications of diagnostic uncertainty that result from inconclusive results generated by newborn bloodspot screening (NBS) for cystic fibrosis (CF). STUDY DESIGN: Using a mixed methods prospective cohort study of children who received NBS for CF, we compared psychosocial outcomes of parents whose children who received persistently inconclusive results with those whose children received true positive or screen-negative results. RESULTS: Mothers of infants who received inconclusive results (n = 17), diagnoses of CF (n = 15), and screen-negative results (n = 411) were surveyed; 23 parent interviews were completed. Compared with mothers of infants with true positive/screen-negative results, mothers of infants with inconclusive results reported greater perceived uncertainty (P < .006) but no differences in anxiety or vulnerability (P > .05). Qualitatively, parents valued being connected to experts but struggled with the meaning of an uncertain diagnosis, worried about their infant's health-related vulnerability, and had mixed views about surveillance. CONCLUSION: Inconclusive CF NBS results were not associated with anxiety or vulnerability but led to health-related uncertainty and qualitative concerns. Findings should be considered alongside efforts to optimize protocols for CF screening and surveillance. Educational and psychosocial supports are warranted for these families.

Life-course partnership history and midlife health behaviours in a population-based birth cohort.

BACKGROUND: Marital and partnership history is strongly associated with health in midlife and later life. However, the role of health behaviours as an explanatory mechanism remains unclear. The aim of this study was to investigate prospective associations between life-course partnership trajectories (taking into account timing, non-marital cohabitation, remarriage and marital transitions) and health behaviours measured in midlife. METHODS: We analysed data from the British National Child Development Study, a prospective cohort study that includes all people born in 1 week of March 1958 (N=10 226). This study included men and women with prospective data on partnership history from age 23 to 42-44 and health behaviours collected at ages 42-46 (2000-2004). Latent class analysis was used to derive longitudinal trajectories of partnership history. We used multivariable regression models to estimate the association between midlife health behaviours and partnership trajectory, adjusting for various early and young adult characteristics. RESULTS: After adjustment for a range of potential selection factors in childhood and early adulthood, we found that problem drinking, heavy drinking and smoking were more common in men and women who experienced divorce or who had never married or cohabited. Women who married later had a lower prevalence of smoking and were less likely to be overweight than those who married earlier. Overall marriage was associated with a higher body mass index. Individuals who never married or cohabited spent less time exercising. CONCLUSIONS: Some aspects of partnership history such as remaining unpartnered and experiencing divorce are associated with more smoking and drinking in midlife, whereas marriage is associated with midlife weight gain. Despite these offsetting influences, differences in health behaviours probably account for much of the association between partnership trajectories and health found in previous studies.

Parent Experience With False-Positive Newborn Screening Results for Cystic Fibrosis.

BACKGROUND: The risk of psychosocial harm in families of infants with false-positive (FP) newborn bloodspot screening (NBS) results for cystic fibrosis (CF) is a longstanding concern. Whether well designed retrieval and confirmatory testing systems can mitigate risks remains unknown. METHODS: Using a mixed-methods cohort design, we obtained prospective self-report data from mothers of infants with FP CF NBS results 2 to 3 months after confirmatory testing at Ontario's largest follow-up center, and from a randomly selected control sample of mothers of screen negative infants from the same region. Mothers completed a questionnaire assessing experience and psychosocial response. A sample of mothers of FP infants completed qualitative interviews. RESULTS: One hundred thirty-four mothers of FP infants (response rate, 55%) and 411 controls (response rate, 47%) completed questionnaires; 54 mothers of FP infants were interviewed. Selected psychosocial response measures did not detect psychosocial distress in newborns or 1 year later (P > .05). Mothers recalled distress during notification of the positive result and in the follow-up testing period related to fear of chronic illness, but valued the screening system of care in mitigating concerns. CONCLUSIONS: Although immediate distress was reported among mothers of FP infants, selected psychometric tools did not detect these concerns. The NBS center from which mothers were recruited minimizes delay between notification and confirmatory testing and ensures trained professionals are communicating results and facilitating follow-up. These factors may explain the presence of minimal psychosocial burden. The screening system reflected herein may be a model for NBS programs working to minimize FP-related psychosocial harm.

Cystic fibrosis gene modifier SLC26A9 modulates airway response to CFTR-directed therapeutics.

Cystic fibrosis is realizing the promise of personalized medicine. Recent advances in drug development that target the causal CFTR directly result in lung function improvement, but variability in response is demanding better prediction of outcomes to improve management decisions. The genetic modifier SLC26A9 contributes to disease severity in the CF pancreas and intestine at birth and here we assess its relationship with disease severity and therapeutic response in the airways. SLC26A9 association with lung disease was assessed in individuals from the Canadian and French CF Gene Modifier consortia with CFTR-gating mutations and in those homozygous for the common Phe508del mutation. Variability in response to a CFTR-directed therapy attributed to SLC26A9 genotype was assessed in Canadian patients with gating mutations. A primary airway model system determined if SLC26A9 shows modification of Phe508del CFTR function upon treatment with a CFTR corrector. In those with gating mutations that retain cell surface-localized CFTR we show that SLC26A9 modifies lung function while this is not the case in individuals homozygous for Phe508del where cell surface expression is lacking. Treatment response to ivacaftor, which aims to improve CFTR-channel opening probability in patients with gating mutations, shows substantial variability in response, 28% of which can be explained by rs7512462 in SLC26A9 (P = 0.0006). When homozygous Phe508del primary bronchial cells are treated to restore surface CFTR, SLC26A9 likewise modifies treatment response (P = 0.02). Our findings indicate that SLC26A9 airway modification requires CFTR at the cell surface, and that a common variant in SLC26A9 may predict response to CFTR-directed therapeutics.