Onset Subgroup Research Articles

Identification of an inflammation-associated psychosis onset subgroup by applying unsupervised machine learning to whole-blood expression levels of immune gene transcripts

Identification of an inflammation-associated psychosis onset subgroup by applying unsupervised machine learning to whole-blood expression levels of immune gene transcripts

Impact of baseline clinical asthma characteristics on the response to mepolizumab: a post hoc meta-analysis of two Phase III trials

BackgroundSevere asthma is associated with a broad range of phenotypes and clinical characteristics. This analysis assessed whether select baseline patient characteristics could prognosticate mepolizumab efficacy in severe eosinophilic asthma.MethodsThis was a post hoc meta-analysis of data from the Phase III MENSA (NCT01691521/MEA115588) and MUSCA (NCT02281318/200862) studies. Patients aged ≥ 12 years with severe eosinophilic asthma and a history of exacerbations were randomised to receive placebo (MENSA/MUSCA), mepolizumab 75 mg intravenously (MENSA) or 100 mg subcutaneously (SC) (MENSA/MUSCA) every 4 weeks for 32 (MENSA) or 24 (MUSCA) weeks. The primary endpoint was the annual rate of clinically significant exacerbations; other outcomes included the proportion of patients with no exacerbations and changes from baseline in pre-bronchodilator forced expiratory volume in 1 s (FEV1), St George’s Respiratory Questionnaire (SGRQ) total score and Asthma Control Questionnaire (ACQ)-5 score. Analyses were performed by baseline age of asthma onset (< 18 years; 18–40 years; ≥ 40 years); lung function (% predicted FEV1 ≤ 60; 60–80; > 80); airway reversibility (reversible [≥ 12% change in FEV1]; non-reversible [< 12% change in FEV1]); perennial and/or seasonal allergen sensitivity (yes/no); asthma control (uncontrolled [ACQ-5 score ≥ 1.5]; partial/complete control [ACQ-5 score < 1.5]).ResultsOverall, 936 patients received mepolizumab 100 mg SC or placebo. Across age at asthma onset, lung function and airway reversibility subgroups, mepolizumab reduced the rate of clinically significant exacerbations by 49–63% versus placebo. Improvements in lung function, SGRQ total score and ACQ-5 score were also seen with mepolizumab versus placebo across most age and lung function subgroups. Clinically significant exacerbations were reduced with mepolizumab versus placebo irrespective of season or allergen sensitivity; SGRQ total and ACQ-5 scores were generally improved across seasons.ConclusionsMepolizumab efficacy was consistent for patients with varying age at asthma onset, lung function, airway reversibility and allergen sensitivities at baseline. Our results indicate that mepolizumab is likely to be beneficial for patients with severe eosinophilic asthma with a broad range of baseline clinical characteristics; large-scale real-world studies are needed to confirm the external validity of these findings.Trial registration Post hoc meta-analysis of data from MENSA (NCT01691521/MEA115588) and MUSCA (NCT02281318/200862)

Childhood maltreatment and metabolic syndrome in bipolar disorders: In search of moderators

As compared to the general population, adult individuals with bipolar disorders (BD) have higher mortality rates due to cardiovascular diseases and higher prevalence of Metabolic Syndrome (MetS). Recent evidence suggests that childhood maltreatment may contribute to the cardiovascular burden in individuals with BD. However, studies are scarce, with limited sample sizes and inconsistent results. We explored the associations between a self-reported history of childhood maltreatment and MetS (and its subcomponents) in a large sample of 2390 individuals with BD. Childhood maltreatment was assessed using the Childhood Trauma Questionnaire and MetS was defined according to the revised criteria of the ATEP III. We suggested associations between childhood maltreatment and the presence of MetS in men and in younger individuals. The association between childhood maltreatment and the presence of MetS in the early onset subgroup was not significant after adjustment for site of recruitment and level of education. Hence, some links between childhood maltreatment and MetS might exist only in specific subgroups of individuals with BD, but confirmation is required in independent and large samples, while taking into account potential confounders. This would help defining how psychosocial interventions that target childhood maltreatment and its consequences may be beneficial for physical health.

Non-Motor Features of Amyotrophic Lateral Sclerosis

Introduction:Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of motor neurons. Spread of pathology to other brain areas leads to development of non-motor symptoms (NMSs). These usually remain undiagnosed because of overwhelming motor problem and are responsible for significant distress to the patient. Our objective was to explore the burden of various NMSs of patients with ALS, compare between limb-onset and bulbar-onset patients, and to correlate with severity and duration of disease.Methods:Fifty patients with ALS diagnosed according to revised El Escorial Criteria and 50 healthy controls were included in this study. They were assessed with NMS Questionnaire, Beck's Depression Inventory, Center for Neurologic Study-Lability Scale, Drooling Frequency and Severity Scale, Epworth Sleepiness scale, Bengali Mental State Examination, and Frontal Assessment Battery and relevant statistical analyses were carried out.Results:The patients with ALS had significantly increased prevalence of almost all NMSs compared to controls. There was also significant increase in depression, suicidal ideation, pseudobulbar affect, and daytime sleepiness in patients with ALS. The bulbar onset subgroup had significantly increased daytime drooling, dysphagia, nausea and vomiting, whereas the limb onset subgroup reported increased frequency of leg swelling. Executive dysfunction was detected in 24% of patients with ALS and 9.8% had mild cognitive impairment. Weight loss, frequency of falling, insomnia, unpleasant nocturnal leg sensations, difficulty having sex, depression, and cognitive impairment increased significantly with an increase in severity of the disease.Conclusion:NMSs were significantly more prevalent in patients with ALS. Some NMSs worsened with advancement of the disease.

Clinical Correlates of Early-Onset Hypertension

BACKGROUNDEarly-onset hypertension has been established as a heritable trait and a risk factor for cardiovascular disease outcomes. However, the clinical correlates of early-onset hypertension remain unidentified.METHODSIn this study, we assessed the demographic characteristics and lifestyle factors related to hypertension onset age in a sample of 3,286 Coronary Artery Risk Development in Young Adults (CARDIA) study participants (mean baseline age 25 ± 4 years, 57% women). We examined the association between the participants’ baseline characteristics and age of hypertension onset subgroups (<35, 35‒44, or ≥45 years) using a multinomial logistic regression model with those who did not develop hypertension as the reference group. Hypertension onset was defined as blood pressure ≥140/90 mm Hg or antihypertensive medication use on 2 consecutively attended follow-up visits.RESULTSIn the multinomial logistic regression model, individuals who were black (odds ratio [OR], 5.08; 95% confidence interval [CI], 3.17–8.14), were more obese (OR, 1.57; 95% CI, 1.32–1.88), or had higher total cholesterol (OR, 1.34; 95% CI, 1.13–1.60 per SD) had increased odds of early-onset hypertension (onset at <35 years) vs. not developing hypertension. In contrast, 1-SD higher high-density lipoprotein (HDL)-cholesterol was related to decreased odds of early-onset hypertension (OR, 0.71; 95% CI, 0.57–0.89). The odds for having earlier hypertension onset increased linearly across age of onset categories in black individuals and individuals with lower HDL-cholesterol (P < 0.05 for trend for both).CONCLUSIONSOur findings suggest that individuals who are black, obese, have higher total cholesterol, or have lower HDL-cholesterol level, are potentially at an increased risk of having early-onset hypertension.

Outcome measures and treatment effectiveness in late onset myasthenia gravis

BackgroundRecently different subtypes of myasthenia gravis (MG) have been described. They differ for clinical features and pathogenesis but the prognosis and response to treatment is less clear. The aim of the study was to evaluate outcome and treatment effectiveness including side effects in late onset MG (LOMG) compared with early onset MG (EOMG).MethodsWe analysed retrospectively 208 MG patients. Clinical features were recorded as well as treatment and side effects. Outcome at the last follow-up was evaluated with MGSTI and MGPIS scales.ResultsThe 208 patients included were classified as follow: 36 ocular MG, 40 EOMG, 72 LOMG, 25 thymoma-associated, 14 anti-MuSK and 21 double seronegative. Similar positive outcome was achieved in either early and late onset subgroup. We found pharmacological remission and minimal manifestations at the MGFA-PIS in the 95% and 94,4% of EOMG and LOMG respectively but in LOMG a lower dose of immunosuppressors (MGSTI< 2) was required compared to EOMG (p = 0,048). Severe side effects were present in a small percentage of patients in both group but diabetes was more frequent in LOMG vs EOMG (2,2% vs 5%, p = 0.017).ConclusionsDespite LOMG has more comorbidities that might interfere with treatment and outcome, therapeutic management does not seem to differ between EOMG and LOMG. A similar positive outcome was seen in both subgroups but LOMG group seems to require lower doses of medication to control symptoms.

Serum Sphingosine 1-Phosphate (S1P): A Novel Diagnostic Biomarker in Early Acute Ischemic Stroke.

Background: Sphingosine 1-phosphate (S1P) is a lipid metabolite that mediates various physiological processes, including vascular endothelial cell function, inflammation, coagulation/thrombosis, and angiogenesis. As a result, S1P may contribute to the pathogenesis of stroke.Objective: This study aimed to evaluate the diagnostic value of serum S1P in acute stroke.Method: A total of 72 patients with ischemic stroke, 36 patients with hemorrhagic stroke, and 65 controls were enrolled. Serum S1P was detected by enzyme-linked immunosorbent assay (ELISA).Results: Receiver operating characteristic curve analysis demonstrated that serum S1P could discriminate ischemic stroke from hemorrhagic stroke in both total population and subgroup analyses of samples obtained within 24 h of symptom onset (subgroup < 24h) (area under curve, AUCTotal = 0.64, P = 0.017; AUCSubgroup < 24h = 0.91, P < 0.001) and controls (AUCTotal = 0.62, P = 0.013; AUCSubgroup <24h = 0.83, P < 0.001). Furthermore, S1P showed higher efficacy than high-density lipoprotein cholesterol (HDL-C) in discriminating ischemic stroke from controls in the total population (PS1P = 0.013, PHDL−C = 0.366) and in the subgroup analysis (i.e., <24 h; PS1P < 0.001, PHDL−C = 0.081). Additionally, lower serum S1P was associated with cervical artery plaques (P = 0.021) in controls and with dyslipidemia (P = 0.036) and milder neurological impairment evaluated by the National Institute of Health Stroke Scale (NIHSS, P = 0.047) in the ischemic stroke group.Conclusions: The present study preliminarily investigated the diagnostic value of serum S1P in acute stroke. Decreased serum S1P may become a potential biomarker for early acute ischemic stroke and can indicate disease severity.

Association analysis of 15 GWAS-linked loci with Parkinson’s disease in Chinese Han population

Genetic factors play an important role in Parkinson’s disease (PD) and vary from different races. A previous genome-wide association study (GWAS) identified 17 novel risk loci that were associated with PD in Caucasians. Several subsequent studies investigated the association between these loci and PD in Chinese populations. However, the results on the role of these variants for PD have been conflicting. To explore the relationship of 15 controversial loci with PD in the Chinese Han population, we performed a case-control study including 492 PD patients and 524 healthy controls. iMLDR technology was used to type 15 GWAS-linked loci of 1016 blood samples from all subjects. We found that rs34043159 (IL1R2) (dominant model after adjusted: p = 0.011, OR 95 % CI 0.577 (0.378–0.880)) and rs4073221 (SATB1) (allele model: p = 0.001, OR 95 % CI 0.542 (0.371–0.792); dominant model after adjusted: p = 0.049, OR 95 % CI 0.587 (0.345–0.998)) were associated with PD. After age onset and gender subgroup analysis, rs34043159 (IL1R2) (χ2 = 7.971, p = 0.019) and rs4073221 (SATB1) (χ2 = 12.673, p = 0.001) were associated with late-onset PD. rs34043159 (IL1R2) was associated with PD in females (χ2 = 7.227, p = 0.027) rather than males (χ2 = 1.100, p = 0.577). rs4073221 (SATB1) was associated with PD in both males (χ2 = 10.270, p = 0.005) and females (χ2 = 7.050, p = 0.022). Further studies are needed to explore the role of IL1R2 and SATB1 in the pathogenesis of PD.

Evaluation of peak or onset latency in the median-versus-ulnar digit four sensory comparison study for diagnosing carpal tunnel syndrome

Aim: Peak or onset latency difference of the median and ulnar nerves can be used in the median-versus-ulnar digit 4 sensory comparison study (MUD4CS) for electrodiagnosis of carpal tunnel syndrome (CTS). This study aimed to investigate the differences in results while using peak or onset latency difference.Material and Methods: The hands of patients with clinical CTS diagnosis but normal median nerve conduction study (NCS) results were included retrospectively in this study. NCSs of the median and ulnar nerves with onset and peak latencies in MUD4CS were recorded. Onset and peak latency differences of the two nerves and also peak-onset latency difference of the median nerve in MUD4CS were calculated. The hands were divided into two groups according to MUD4CS findings: abnormal and normal. The hands in the abnormal group were also divided into peak and onset subgroups.Results: A total of 277 hands were included in this study. Abnormal MUD4CS results were observed in 103 hands; 77 hands based on onset latency difference, and in 76 hands based on peak latency difference. Median sensory conduction velocity was slower and amplitude was smaller in the abnormal group than in the normal group (p=0.003, p=0.027 respectively). Median peak-onset latency difference was significantly greater in the peak subgroup than in the onset subgroup (p=0.0001).Conclusion: It may be more useful to measure both peak and onset latency differences when diagnosing CTS because some cases may be overlooked by using a single latency difference.

The C9orf72 expansion is associated with accelerated respiratory function decline in a large Amyotrophic Lateral Sclerosis cohort

Introduction: The C9orf72 hexanucleotide repeat expansion is causal in amyotrophic lateral sclerosis (ALS) and has a negative effect on prognosis. The C9orf72 repeat expansion has been associated with an accelerated deterioration of respiratory function and survival in a cohort of 372 Portuguese patients. Methods: Cases presenting to the Irish ALS clinic with both longitudinal occluded sniff nasal inspiratory pressure (SNIP) and C9orf72 testing were including in the study. Clinical variables and survival characteristics of these patients were collected. Joint longitudinal and time to event models were constructed to explore the longitudinal characteristics of the cohort by C9orf72 status. Results: In total, 630 cases were included, of which 58 (9.2%) carried the C9orf72 repeat expansion. Plots of the longitudinal trend after joint modelling revealed that those carrying the expansion had worse respiratory function throughout the course of their disease than those without. The ALS Functional Rating Scale-revised (ALSFRS-R) respiratory sub-score did not distinguish C9orf72 normal from expanded cases. Furthermore, modelling by site of onset and gender sub-groups revealed that this difference was greatest in male spinal onset cases. Joint models further indicated that occluded SNIP values were of prognostic importance. Conclusions: Our results confirm findings from Portugal that the C9orf72 repeat expansion is associated with accelerated respiratory function decline. Analysis via joint models indicate that respiratory function is of prognostic importance and may explain previous observations of poorer prognosis in male spinal onset patients carrying the C9orf72 expansion.

The C9orf72 expansion is associated with accelerated respiratory function decline in a large Amyotrophic Lateral Sclerosis cohort.

Introduction: The C9orf72 hexanucleotide repeat expansion is causal in amyotrophic lateral sclerosis (ALS) and has a negative effect on prognosis. The C9orf72 repeat expansion has been associated with an accelerated deterioration of respiratory function and survival in a cohort of 372 Portuguese patients. Methods: Cases presenting to the Irish ALS clinic with both longitudinal occluded sniff nasal inspiratory pressure (SNIP) and C9orf72 testing were including in the study. Clinical variables and survival characteristics of these patients were collected. Joint longitudinal and time to event models were constructed to explore the longitudinal characteristics of the cohort by C9orf72 status. Results: In total, 630 cases were included, of which 58 (9.2%) carried the C9orf72 repeat expansion. Plots of the longitudinal trend after joint modelling revealed that those carrying the expansion had worse respiratory function throughout the course of their disease than those without. The ALS Functional Rating Scale-revised (ALSFRS-R) respiratory sub-score did not distinguish C9orf72 normal from expanded cases. Furthermore, modelling by site of onset and gender sub-groups revealed that this difference was greatest in male spinal onset cases. Joint models further indicated that occluded SNIP values were of prognostic importance. Conclusions: Our results confirm findings from Portugal that the C9orf72 repeat expansion is associated with accelerated respiratory function decline. Analysis via joint models indicate that respiratory function is of prognostic importance and may explain previous observations of poorer prognosis in male spinal onset patients carrying the C9orf72 expansion.

Association between CTLA-4 gene polymorphism and myasthenia gravis in a Chinese cohort

Abnormal CTLA-4 expression is involved in the development of myasthenia gravis (MG), and serum CTLA-4 levels are positively correlated with serum anti-AChR antibody concentration, which might be related with the severity of MG. Polymorphism in CTLA-4 gene is associated with various autoimmune disorders. We investigated the association of polymorphism in CTLA-4 gene with the clinical variables and severity of MG. The frequencies of alleles and genotypes were compared between 480 MG patients and 487 healthy controls, as well as among subgroups of MG patients. The frequency of rs733618*C allele is significantly higher in MG group and several subgroups than in control group. Genotype is not found as independent factor for essential clinical variables of MG. The frequency of rs231775*A allele is significantly lower in ocular onset subgroup than in control group, and the frequencies of rs231775*A allele and rs3087243*A allele are significantly lower in ocular onset subgroup than in generalized onset subgroup. Genotypes of the two SNPs are found as independent factors for ocular onset. The frequency of rs231775*A allele is significantly lower in mild subgroup than that in control group. Genotype is not found as independent factor for mild severity. A haplotype containing rs733618*C, rs231775*G and rs3087243*G is identified to increase the general risk of MG by 1.278-fold and ocular onset MG subgroup by 1.362-fold. There is association of rs733618 with the general susceptibility of MG, and association of rs231775 and rs3087243 with the susceptibility of ocular onset MG, but no association with the severity of MG.

Clinicopathologic and Racial/Ethnic Differences of Colorectal Cancer Among Adolescents and Young Adults.

OBJECTIVES:Despite overall reductions in colorectal cancer burden, incidence rates continue to rise among younger patients, and causes remain unknown. We examined differences in clinicopathologic and racial/ethnic characteristics within the adolescent and young adult (AYA) population diagnosed with colorectal cancer in the United States.METHODS:Using the National Cancer Institute's Surveillance, Epidemiology, and End Results program data, we identified individuals diagnosed with first primary colorectal cancer between ages 15 and 39 years from 2010 to 2015. Adjusted multivariable logistic regression models were used to quantify clinicopathologic and racial/ethnic differences across age at onset subgroups (15–19, 20–24, 25–29, 30–34, and 35–39 years).RESULTS:We identified 5,350 AYA patients diagnosed with colorectal cancer. Of note, 28.6% of AYA cases were diagnosed with right-sided tumors (cecum to transverse colon). The proportion of right-sided colorectal cancers differed significantly by age group at diagnosis (38.3% vs 27.3% of AYAs aged 15–19 vs 35–39 years, respectively; P trend = 0.01). Proportions of cases with mucinous adenocarcinoma and signet ring cell carcinoma histopathologic subtypes significantly increased with younger age at onset (P trends = 0.01 and 0.03, respectively). Differences in clinical stage were observed across AYA age groups, with stage II disease increasing with younger age (P trend = 0.01). The proportion of Hispanic AYAs was higher within younger patients, accounting for 21.0% of the AYA population aged 35–39 years up to 28.3% of 15–19-year-old individuals (P trend = 0.003).DISCUSSION:Within the AYA population, colorectal cancers differ by clinicopathologic and racial/ethnic characteristics. Further investigation of the clinical and biologic diversity of colorectal cancers that partially underlie age- and race-related differences in cancer susceptibility and outcomes is warranted.

Interleukin-23 receptor (IL-23R) gene polymorphisms and haplotypes associated with the risk of preeclampsia: evidence from cross-sectional and in silico studies.

Pre-eclampsia is a relatively common pregnancy disorder. Serum concentrations of certain pro-inflammatory molecules and cytokines like interleukin-23 may affect the pathogenesis of pre-eclampsia. The interleukin-23 receptor (IL-23R) gene plays an important role in the progression of inflammatory and autoimmune diseases and IL-23 polymorphisms might influence the susceptibility of pre-eclampsia. The aim of the recent study was to establish the association between IL-23R gene polymorphisms and the susceptibility for developing of pre-eclampsia. One hundred and fifty-eight pregnant patients with pre-eclampsia and 153 controls were genotyped using RFLP-PCR and AS-PCR. Also, an in silico analysis was performed to predict possible effects of these variations on IL-23R mRNA and protein structures. The frequency of the AG genotype of rs11209026 is related to a higher risk of pre-eclampsia. The mutant C and A allele in rs10889677 and rs11209026 SNPs, respectively, are correlated with the risk of pre-eclampsia and they are more frequent in severe late onset PE. We found higher frequency of the haplotype CG in patients with pre-eclampsia in comparison to healthy controls, as well as, the CG haplotype frequency significantly increased the risk of PE in severe, early onset, and late onset sub-groups. The results of computational analysis predicted rs11209026 and rs10889677 SNPs as functional variations, which can influence IL-23R mRNA and protein. The results of present study show positive association between polymorphisms in the IL-23R gene and pre-eclampsia. Therefore, the presence of IL-23R rs11209026, rs10889677 polymorphism might be markers for the genetic susceptibility to pre-eclampsia.

Genetic and Clinical Findings in a Large Cohort of Chinese Patients with Suspected Retinitis Pigmentosa

To characterize the genetic landscape of patients with suspected retinitis pigmentosa (RP) in the Chinese population. Cohort study. A total of 1243 patients of Chinese origin with clinically suspected RP and their available family members (n= 2701) were recruited. All patients and available family members were screened using multigene panel testing (including 586 eye disease-associated genes), followed by clinical variant interpretation. Diagnostic yield, the 17 most commonly implicated genes, age at onset, de novo mutations, and clinical usefulness of genetic testing. Overall, 72.08% of patients received a molecular diagnosis, and the 17 top genes covered 75.63% of diagnostic cases. Diagnostic yield was higher among patients in the early-onset subgroup (≤5 years old, 79.58%) than in the childhood or adolescence-onset subgroup (6-16 years old, 73.74%) and late-onset subgroup (≥17 years old, 65.99%). Moreover, different genes associated with different onset ages and subgroups with different onset ages showed a diverse mutation spectrum. Only 11 de novo mutations (3.18%) were identified. Furthermore, 16.84% of the patients who received a molecular diagnosis had refinement of the initial clinical diagnoses, and the remaining 83.16% received definite genetic subtypes of RP. This large cohort study provides population-based data of the genome landscape of patients with suspected RP in China. The diagnostic yield was significantly higher than that in previous studies, and the mutation spectrum is completely different with other populations. Genetic testing improves the chance to establish a precise diagnosis, identifies features not previously determined, and allows a more accurate refinement of risk to family members. Our results not only expand the existing genotypic spectrum but also serve as an efficient reference for the design of panel-based genetic diagnostic testing and genetic counseling for patients with suspected RP in China.

M24 - EFFECTS OF SCHIZOPHRENIA AND BIPOLAR POLYGENIC RISK SCORES ON AGE AT ONSET IN BIPOLAR DISORDER

Background Patients with early age at onset (AAO) Bipolar Disorder (BD) are characterized by a higher recurrence rate of mood episodes, higher number of suicide attempts, more severe psychotic symptoms and neurocognitive impairments and a poor long-term prognosis (Aminoff et al. 2013). Results of previous studies investigating the genetic background of AAO in BD provide some evidence that early AAO might be, to a certain degree, genetically determined. (Lin et al. 2006, Craddock et al. 2014) The aim of this study was to investigate whether earlier disease onset in BD might be a consequence of a higher cumulative BD or Schizophrenia (SCZ) genetic risk. Methods Data of DSM-III or IV BD patients (N=1980) was pooled from three large, international studies: from the Consortium of Lithium Genetics (ConLiGen) dataset, from the PsyCourse study and from the BoMa sample. AAO was defined as the age at the first mood episode. Different AAO subgroups were identified with admixture analysis and the likelihood of AAO-group membership was expressed with posterior probability values. All individuals were genotyped on whole-genome SNP arrays and their SCZ- and BD- polygenic risk scores (PRS) at 11 different p-value thresholds (pTs) (pT1=0.00000005, pT11=1) were calculated using data from SCZ PGC2 and BD-PGC as training data sets. The associations between the SCZ- and BD-PRSs and AAO were evaluated with linear regression, whereas the AAO scores of the identified AAO-groups were compared with ANOVA. Results The cumulative polygenic risk for bipolar disorder was significantly associated with age of onset (R2 change) at more liberal p-value thresholds. No association was found between AAO and SCZ-PRS. Three different BD-AAO subgroups (mean: 17.42, 22.07, 39.49) were identified with admixture analysis. The identified groups did not differ in terms of their SCZ-PRS and BD-PRS. Discussion Our results suggest that the accumulation of bipolar disorder-associated alleles in individuals with earlier disease onset could be a possible explanation for the observed genetic determination of age of onset in bipolar disorder. However, this explains only a small proportion of the phenotype implying that other factors may be of greater relevance. Similar to previous studies, we could identify three different age of onset subgroups in bipolar disorder using admixture analysis. These groups were previously validated based on phenotypic differences, however no data has been available on their genetic and molecular characteristics. Nevertheless, we found no group difference in terms of genetic risk for schizophrenia and bipolar disorder.

Age at onset of first suicide attempt: Exploring the utility of a potential candidate variable to subgroup attempters.

Our objective was to explore the utility of age at first suicide attempt in identifying subgroups of suicide attempters. In a retrospective study design, we collected information from the clinical charts of 895 patients assessed over a seven-year period. Admixture analysis was used to determine the best fitting theoretical model for distribution of age at first attempt that divided the sample. Subsequently, multivariate analysis was performed to identify variables that distinguished the subgroups identified. The theoretical solution that best explained the observed distribution of age at first suicide attempt was a mixture of two Gaussian distributions with a cut-off of 31 years for the two subgroups. In logistic regression analysis, male gender (Odds ratios [OR] 3.047, 95% Confidence Interval (CI) 1.818-5.106), fewer years of formal schooling (OR 3.384, 95% CI 1.701-6.734) and being married (OR 23.36, 95% CI 10.753-50.000), were more commonly associated with the late onset subgroup (age at first attempt >31 years). Further, the late onset subgroup had poorer global functioning (OR 0.980, 95% CI 0.962 to 0.998). Age at onset of first suicide attempt is a useful candidate marker to delineate an early and late onset subgroup among suicide attempters. These results are likely to inform customization of suicide prevention strategies.

New insights into early and late onset subgroups of preeclampsia from longitudinal versus cross-sectional analysis of urinary inositol-phosphoglycan P-Type

Most pre-eclampsia (PE) studies have used cross-sectional data to derive conclusions regarding the pathophysiology of the condition. This has led to the concept that there exists early (<34 weeks) and late-onset (>34 weeks) disease according to gestational age at diagnosis. Survival time models have predicted that if the pregnancy was to continue indefinitely, all women would develop PE. In this study we have performed a longitudinal analysis of the urinary biomarker, inositol phosphoglycan (IPG), in a cohort of women giving birth in Mauritius (n-920). We have analysed the PE data in the traditional cross-sectional manner for n = 77 women who developed PE and also then looked at the longitudinal data for 71/77 of the same women. The data allows us to use longitudinal values to calculate a date of onset (first presence of biomarker in urine) and compare that to date of clinical diagnosis (cross sectional). We find two populations for both analysis consistent with an early and late stage subgroup. The calculated date of onset had subgroups (early and late) at 28.4 ± 0.41 weeks and 35.37 ± 0.26 weeks and for clinical date of diagnosis, 32.3 ± 0.59 weeks and 37.04 ± 0.62 weeks, respectively. The presence of the same biomarker in both subgroups and its ability to predict clinical onset 2–4 weeks prior to clinical diagnosis suggest that both groups may have similar aetiology.

Spectrum of mutations in monogenic diabetes genes identified from high-throughput DNA sequencing of 6888 individuals

BackgroundDiagnosis of monogenic as well as atypical forms of diabetes mellitus has important clinical implications for their specific diagnosis, prognosis, and targeted treatment. Single gene mutations that affect beta-cell function represent 1–2% of all cases of diabetes. However, phenotypic heterogeneity and lack of family history of diabetes can limit the diagnosis of monogenic forms of diabetes. Next-generation sequencing technologies provide an excellent opportunity to screen large numbers of individuals with a diagnosis of diabetes for mutations in disease-associated genes.MethodsWe utilized a targeted sequencing approach using the Illumina HiSeq to perform a case-control sequencing study of 22 monogenic diabetes genes in 4016 individuals with type 2 diabetes (including 1346 individuals diagnosed before the age of 40 years) and 2872 controls. We analyzed protein-coding variants identified from the sequence data and compared the frequencies of pathogenic variants (protein-truncating variants and missense variants) between the cases and controls.ResultsA total of 40 individuals with diabetes (1.8% of early onset sub-group and 0.6% of adult onset sub-group) were carriers of known pathogenic missense variants in the GCK, HNF1A, HNF4A, ABCC8, and INS genes. In addition, heterozygous protein truncating mutations were detected in the GCK, HNF1A, and HNF1B genes in seven individuals with diabetes. Rare missense mutations in the GCK gene were significantly over-represented in individuals with diabetes (0.5% carrier frequency) compared to controls (0.035%). One individual with early onset diabetes was homozygous for a rare pathogenic missense variant in the WFS1 gene but did not have the additional phenotypes associated with Wolfram syndrome.ConclusionTargeted sequencing of genes linked with monogenic diabetes can identify disease-relevant mutations in individuals diagnosed with type 2 diabetes not suspected of having monogenic forms of the disease. Our data suggests that GCK-MODY frequently masquerades as classical type 2 diabetes. The results confirm that MODY is under-diagnosed, particularly in individuals presenting with early onset diabetes and clinically labeled as type 2 diabetes; thus, sequencing of all monogenic diabetes genes should be routinely considered in such individuals. Genetic information can provide a specific diagnosis, inform disease prognosis and may help to better stratify treatment plans.

Correlations between slow-rate repetitive nerve stimulation and characteristics associated with amyotrophic lateral sclerosis in Chinese patients.

[Purpose] To clarify the features associated with decrements in compound muscle action potentials (CMAP) during slow-rate repetitive nerve stimulation (RNS) of muscles involved in amyotrophic lateral sclerosis (ALS) in mainland China. [Subjects and Methods] A retrospective study of decremental responses to slow-rate RNS was performed to compare patients with ALS to those with myasthenia gravis (MG). [Results] A significant decrement (>5%) was observed in at least one muscle in 54% of ALS patients. The trapezius muscle was the most commonly affected (67%). In the ALS group, the CMAP amplitude evoked by the first stimulus was negatively correlated with the CMAP decrement in ulnar but not accessory nerves. Additionally, a positive decrement was associated with disease progression but not gender, age at onset, disease duration, region of onset, ALSFRS-R scores, or ALS diagnostic subgroup in ALS. Furthermore, the incidence of positive decrements and the decremental percentages were significantly higher in myasthenia gravis (MG) than in ALS. [Conclusions] The lower CMAP amplitude by the first RNS stimulus was more likely to induce a positive decrement in the ulnar nerve in ALS patients. The positive decremental responses to RNS observed in ALS indicate the faster progress of the disease, which is helpful for evaluating prognoses.