Risk Of False-positive Findings Research Articles

Removing outliers from the normative database improves regional atrophy detection in single-subject voxel-based morphometry

PurposeSingle-subject voxel-based morphometry (VBM) compares an individual T1-weighted MRI to a sample of normal MRI in a normative database (NDB) to detect regional atrophy. Outliers in the NDB might result in reduced sensitivity of VBM. The primary aim of the current study was to propose a method for outlier removal (“NDB cleaning”) and to test its impact on the performance of VBM for detection of Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD).MethodsT1-weighted MRI of 81 patients with biomarker-confirmed AD (n = 51) or FTLD (n = 30) and 37 healthy subjects with simultaneous FDG-PET/MRI were included as test dataset. Two different NDBs were used: a scanner-specific NDB (37 healthy controls from the test dataset) and a non-scanner-specific NDB comprising 164 normal T1-weighted MRI from 164 different MRI scanners. Three different quality metrics based on leave-one-out testing of the scans in the NDB were implemented. A scan was removed if it was an outlier with respect to one or more quality metrics. VBM maps generated with and without NDB cleaning were assessed visually for the presence of AD or FTLD.ResultsSpecificity of visual interpretation of the VBM maps for detection of AD or FTLD was 100% in all settings. Sensitivity was increased by NDB cleaning with both NDBs. The effect was statistically significant for the multiple-scanner NDB (from 0.47 [95%-CI 0.36–0.58] to 0.61 [0.49–0.71]).ConclusionNDB cleaning has the potential to improve the sensitivity of VBM for the detection of AD or FTLD without increasing the risk of false positive findings.

Using multiple outcomes in intervention studies: improving power while controlling type I errors

Background The CONSORT guidelines for clinical trials recommend use of a single primary outcome, to guard against the raised risk of false positive findings when multiple measures are considered. It is, however, possible to include a suite of multiple outcomes in an intervention study, while controlling the familywise error rate, if the criterion for rejecting the null hypothesis specifies that N or more of the outcomes reach an agreed level of statistical significance, where N depends on the total number of outcome measures included in the study, and the correlation between them. Methods Simulations were run, using a conventional null-hypothesis significance testing approach with alpha set at .05, to explore the case when between 2 and 12 outcome measures are included to compare two groups, with average correlation between measures ranging from zero to .8, and true effect size ranging from 0 to .7. In step 1, a table is created giving the minimum N significant outcomes (MinNSig) that is required for a given set of outcome measures to control the familywise error rate at 5%. In step 2, data are simulated using MinNSig values for each set of correlated outcomes and the resulting proportion of significant results is computed for different sample sizes,correlations, and effect sizes. Results The Adjust NVar approach can achieve a more efficient trade-off between power and type I error rate than use of a single outcome when there are three or more moderately intercorrelated outcome variables. Conclusions Where it is feasible to have a suite of moderately correlated outcome measures, then this might be a more efficient approach than reliance on a single primary outcome measure in an intervention study. In effect, it builds in an internal replication to the study. This approach can also be used to evaluate published intervention studies.

Sex-specific diagnostic efficacy of MRI in axial spondyloarthritis: challenging the ‘One Size Fits All’ notion

ObjectivesSex-specific differences in the presentation of axial spondyloarthritis (axSpA) may contribute to a diagnostic delay in women. The aim of this study was to investigate the diagnostic performance of MRI...

Subgroup analyses in clinical research: too tempting?

In many biomedical studies, subgroup analyses are performed to identify subgroups of patients in whom a treatment is most effective, or a risk factor has the largest effect. While both are referred to as subgroup analysis, it is important to distinguish between the estimation of effects within subgroups and the comparison of effects across subgroups. Both are discussed, and we outline the implications regarding sample size and statistical methods for estimation of effects. Also, the risk of false-positive findings-which potentially increases with subgroup analysis-is discussed, as well as the distinction between effect modification and interaction.

The athlete's ECG : What is normal or abnormal?

The electrocardiogram (ECG) has become amobile and cost-effective routine assessment tool to risk stratify leisure-time and professional athletes during preparticipation screening. A central goal is the reduction of sudden cardiac death in sports through early recognition of the most prevalent underlying cardiac pathologies, e.g., hereditary cardiomyopathies or primary arrhythmias. Continuous evolution of the first ECG criteria for athletes, presented in 2010 by the European Society of Cardiology (ESC), has helped to improve the specificity of the criteria to both detect cardiac pathologies in early stages and differentiate from physiologic adaptation of the athlete's heart. Thus, the risk of false-positive findings and erroneous stigmatizations of athletes has been successfully reduced. This review article intends to trace back the changes of the ECG criteria in the light of agrowing body of scientific evidence over the last 15years, to present the key messages of the current International ECG criteria from 2017 and to identify some of the remaining challenges that wait to be answered by physicians in the field of sports medicine and sports cardiology.

How Dropping Subjects Who Failed Manipulation Checks Can Bias Your Results: An Illustrative Case

AbstractManipulations checks are postexperimental measures widely used to verify that subjects understood the treatment. Some researchers drop subjects who failed manipulation checks in order to limit the analyses to attentive subjects. This short report offers a novel illustration on how this practice may bias experimental results: in the present case, through confirming a hypothesis that is likely false. In a survey experiment, subjects were primed with a fictional news story depicting an economic decline versus prosperity. Subjects were then asked whether the news story depicted an economic decline or prosperity. Results indicate that responses to this manipulation check captured subjects’ preexisting beliefs about the economic situation. As a consequence, dropping subjects who failed the manipulation check mixes the effects of preexisting and induced beliefs, increasing the risk of false positive findings. Researchers should avoid dropping subjects based on posttreatment measures and rely on pretreatment measures of attentiveness.

Accurate Screening for Early-Stage Breast Cancer by Detection and Profiling of Circulating Tumor Cells.

Simple SummaryDetection of breast cancer in the early stages is associated with higher cure rates and better survival, and also requires fewer intensive treatments. Current breast cancer screening via mammography is unsuitable for use among (younger) women with more dense breasts, and also has limitations in its ability to detect aggressive breast cancers. In this research article, we describe a breast cancer detection test that is based on the detection of ‘circulating tumor cells’ in blood samples. This test can detect breast cancer CTCs with high accuracy across all age groups, hormone receptor subtypes, histological subtypes, and disease grade. In our study, this test detected breast cancer cases and differentiated them from healthy (cancer-free) females as well as those with non-cancerous conditions with high accuracy. This test has negligible risk of false positive findings, as well as high detection rate for early-stage (localized) breast cancer. Clinical adoption of this test can be beneficial in cancer screening as well as in detection of breast cancers in suspected cases.Background: The early detection of breast cancer (BrC) is associated with improved survival. We describe a blood-based breast cancer detection test based on functional enrichment of breast-adenocarcinoma-associated circulating tumor cells (BrAD-CTCs) and their identification via multiplexed fluorescence immunocytochemistry (ICC) profiling for GCDFP15, GATA3, EpCAM, PanCK, and CD45 status. Methods: The ability of the test to differentiate BrC cases (N = 548) from healthy women (N = 9632) was evaluated in a case–control clinical study. The ability of the test to differentiate BrC cases from those with benign breast conditions was evaluated in a prospective clinical study of women (N = 141) suspected of BrC. Results: The test accurately detects BrAD-CTCs in breast cancers, irrespective of age, ethnicity, disease stage, grade, or hormone receptor status. Analytical validation established the high accuracy and reliability of the test under intended use conditions. The test detects and differentiates BrC cases from healthy women with 100% specificity and 92.07% overall sensitivity in a case–control study. In a prospective clinical study, the test shows 93.1% specificity and 94.64% overall sensitivity in differentiating breast cancer cases (N = 112) from benign breast conditions (N = 29). Conclusion: The findings reported in this manuscript support the clinical potential of this test for blood-based BrC detection.

Biomarker LEPRE1 induces pelitinib-specific drug responsiveness by regulating ABCG2 expression and tumor transition states in human leukemia and lung cancer

Biomarkers for treatment sensitivity or drug resistance used in precision medicine include prognostic and predictive molecules, critical factors in selecting appropriate treatment protocols and improving survival rates. However, identification of accurate biomarkers remain challenging due to the high risk of false-positive findings and lack of functional validation results for each biomarker. Here, we discovered a mechanical correlation between leucine proline-enriched proteoglycan 1 (LEPRE1) and pelitinib drug sensitivity using in silico statistical methods and confirmed the correlation in acute myeloid leukemia (AML) and A549 lung cancer cells. We determined that high LEPRE1 levels induce protein kinase B activation, overexpression of ATP-binding cassette superfamily G member 2 (ABCG2) and E-cadherin, and cell colonization, resulting in a cancer stem cell-like phenotype. Sensitivity to pelitinib increases in LEPRE1-overexpressing cells due to the reversing effect of ABCG2 upregulation. LEPRE1 silencing induces pelitinib resistance and promotes epithelial-to-mesenchymal transition through actin rearrangement via a series of Src/ERK/cofilin cascades. The in silico results identified a mechanistic relationship between LEPRE1 and pelitinib drug sensitivity, confirmed in two cancer types. This study demonstrates the potential of LEPRE1 as a biomarker in cancer through in-silico prediction and in vitro experiments supporting the clinical development of personalized medicine strategies based on bioinformatics findings.

Twinkle artifact in renal ultrasound, is it a solid point for the diagnosis of renal stone in children?

Background: Twinkle artifact, also known as color Doppler comet-tail artifact, occurs behind very strong, granular, and irregular reflecting interfaces such as crystals, stones, or calcification. This is visualized as a random mixture of red and blue pixels in the high-frequency shift spectrum located deep to the interface. Study results have suggested that the sonographic twinkling artifact may aid in the detection of renal stones with a variety of reference standard imaging modalities, including abdominal radiography, excretory urography, gray-scale sonography, and CT. Material and methods: Our retrospective observational study included children who had undergone abdomen/renal ultrasound for kidneys stones in our radiology department between 2013 and 2019. Presence of the twinkle artifact, and stone numbers and sizes were documented. CT examinations done <3 months prior to or after US were retrospectively assessed to confirm the presence of kidney stones as a reference standard. Results: Thirty-three abdominal renal US scans of 33 patients (21 males, 12 females) fulfilled the entry criteria. The interval between the US and CT was <3 months for all patients. The median overall age of the patients was 4 years (IQR: 3.125, range: 1– 165 months), The median number of days between the US and CT was 13 (IQR: 26, range: 0–81 days). US detected 33 hyperechoic foci suspected to be stones; 26 were confirmed as true positive (i.e. showed the twinkle artifact and were seen in CT), 4 were false positive (showed the twinkle artifact but were not seen in CT), and 3 were false negative (did not show the twinkle artifact but were seen in CT). The overall median stone size was 2 mm in the right kidney, and 5 mm in the left kidney (IQR: 6,11 mm), respectively. Twinkle artifact sensitivity was found to be 89.7% (95% CI 39.574%–90%). The twinkle artifact was assessed in all true-positive stones, determining a relatively high PPV of 26/29 (86.7%) for the twinkle artifact. The twinkle artifact was not dependent on stone size. Specificity for the twinkle artifact could not be calculated due to a lack of true negatives. Conclusion: The twinkle artifact is a sensitive US tool for detecting pediatric kidney and ureter stones, but with a small risk of false positive findings.

Using multiple outcomes in intervention studies for improved trade-off between power and type I errors: the Adjust NVar approach

Background The CONSORT guidelines for clinical trials recommend use of a single primary outcome, to guard against the raised risk of false positive findings when multiple measures are considered. It is, however, possible to include a suite of multiple outcomes in an intervention study, while controlling the familywise error rate, if the criterion for rejecting the null hypothesis specifies that N or more of the outcomes reach an agreed level of statistical significance, where N depends on the total number of outcome measures included in the study, and the correlation between them. Methods Simulations were run, using a conventional null-hypothesis significance testing approach with alpha set at .05, to explore the case when between 2 and 12 outcome measures are included to compare two groups, with average correlation between measures ranging from zero to .8, and true effect size ranging from 0 to .7. In step 1, a table is created giving the minimum N significant outcomes (MinNSig) that is required for a given set of outcome measures to control the familywise error rate at 5%. In step 2, data are simulated usingMinNSigvalues for each set of correlated outcomes and the resulting proportion of significant results is computed for different samplesizes,correlations, and effect sizes. Results The AdjustNVarapproach can achieve a more efficient trade-off between power and type I error rate than use of a single outcome when there are three or more moderately intercorrelated outcome variables. Conclusions Where it is feasible to have a suite of moderately correlated outcome measures, then this might be a more efficient approach than reliance on a single primary outcome measure in an intervention study. In effect, it builds in an internal replication to the study. This approach can also be used to evaluate published intervention studies.

Editors' Note: Asymptomatic Optic Nerve Lesions: An Underestimated Cause of Silent Retinal Atrophy in MS

Editors' Note: Asymptomatic Optic Nerve Lesions: An Underestimated Cause of Silent Retinal Atrophy in MS

Let's Get Real about Molecular Breast Imaging and Radiation Risk.

Let's Get Real about Molecular Breast Imaging and Radiation Risk.

Acoustic shadowing in pediatric kidney stone ultrasound: a retrospective study with non-enhanced computed tomography as reference standard.

The usefulness of acoustic shadowing as a feature of pediatric kidney stone ultrasound (US) may be underestimated. The hypothesis was that the majority of stones in children have acoustic shadowing and that its specificity is high (>90%) in pediatric kidney stones. Our retrospective observational study included children who had undergone abdominal non-enhanced computed tomography (CT) for kidney stones in a pediatric renal stone referral centre between 2015 and 2016. US examinations prior to CT were retrospectively assessed for US features such as acoustic shadowing, twinkle artifact and stone size. These features were compared to CT as reference standard. Thirty-one patients (median age: 13years, range: 1-17years) with 77 suspected kidney stones were included. The median stone size was 5mm (interquartile range [IQR]: 5mm). For acoustic shadowing, sensitivity was 70% (95% confidence interval [CI] 56-80%) and specificity was 100% (95% CI 56-100%). All kidney stones with a diameter ≥9mm demonstrated shadowing. Sensitivity for twinkle artifact was 88% (95% CI 72-96%), but specificity for twinkle artifact could not be calculated due to the lack of true negatives. All false-positive stones on US demonstrated twinkle artifact, but none showed shadowing. Acoustic shadowing was demonstrated in the majority of pediatric kidney stones. Specificity was high, but this was not significant. Twinkle artifact is a sensitive US tool for detecting (pediatric) kidney calculi, but with a risk of false-positive findings.

Amount of fibroglandular tissue FGT and background parenchymal enhancement BPE in relation to breast cancer risk and false positives in a breast MRI screening program

ObjectivesThe purpose of this study is to evaluate the predictive value of the amount of fibroglandular tissue (FGT) and background parenchymal enhancement (BPE), measured at baseline on breast MRI, for breast cancer development and risk of false-positive findings in women at increased risk for breast cancer.MethodsNegative baseline MRI scans of 1533 women participating in a screening program for women at increased risk for breast cancer between January 1, 2003, and January 1, 2014, were selected. Automated tools based on deep learning were used to obtain quantitative measures of FGT and BPE. Logistic regression using forward selection was used to assess relationships between FGT, BPE, cancer detection, false-positive recall, and false-positive biopsy.ResultsSixty cancers were detected in follow-up. FGT was only associated to short-term cancer risk; BPE was not associated with cancer risk. High FGT and BPE did lead to more false-positive recalls at baseline (OR 1.259, p = 0.050, and OR 1.475, p = 0.003) and to more frequent false-positive biopsies at baseline (OR 1.315, p = 0.049, and OR 1.807, p = 0.002), but were not predictive for false-positive findings in subsequent screening rounds.ConclusionsFGT and BPE, measured on baseline MRI, are not predictive for overall breast cancer development in women at increased risk. High FGT and BPE lead to more false-positive findings at baseline.Key Points• Amount of fibroglandular tissue is only predictive for short-term breast cancer risk in women at increased risk.• Background parenchymal enhancement measured on baseline MRI is not predictive for breast cancer development in women at increased risk.• High amount of fibroglandular tissue and background parenchymal enhancement lead to more false-positive findings at baseline MRI.

Clinical-grade gene curation strategy in the development of short stature related gene panel by next generation sequencing

Objective Design short stature panel with gene curration strategy. Methods The gene curation process was introduced in detail. The strength of a gene-disease relationship was evaluated based on publicly available genetic and experimental evidence. This process in short stature panel design and its effect on gene selection was further demonstrated. Results After gene curation, the number of gene in list was effectively decreased from 1 276 to 705. The panel sequencing reached a diagnosis rate of 19.7% among a cohort of 371 nation-wide ascertained short stature patients. The gene curation process reduced the risk of false positive findings and decreased diagnostic cost and working hours without affecting the diagnosis rate. Conclusion Gene curation is an important step for NGS-based test and should be widely exercised.(Chin J Lab Med, 2017, 40: 500-504) Key words: Growth disorders; High-throughput nucleotide sequencing; Molecular diagnostic techniques

Genes Involved in Neurodevelopment, Neuroplasticity, and Bipolar Disorder: CACNA1C, CHRNA1, and MAPK1

Background: Bipolar disorder (BPD) is a common and severe mental disorder. The involvement of genetic factors in the pathophysiology of BPD is well known. In the present study, we tested the association of several single-nucleotide polymorphisms (SNPs) within 3 strong candidate genes (CACNA1C, CHRNA7, and MAPK1) with BPD. These genes are involved in monoamine-related pathways, as well as in dendrite development, neuronal survival, synaptic plasticity, and memory/learning. Methods: One hundred and thirty-two subjects diagnosed with BPD and 326 healthy controls of Korean ancestry were genotyped for 40 SNPs within CACNA1C, CHRNA17, and MAPK1. Distribution of alleles and block of haplotypes within each gene were compared in cases and controls. Interactions between variants in different loci were also tested. Results: Significant differences in the distribution of alleles between the cases and controls were detected for rs1016388 within CACNA1C, rs1514250, rs2337980, rs6494223, rs3826029 and rs4779565 within CHRNA7, and rs8136867 within MAPK1. Haplotype analyses also confirmed an involvement of variations within these genes in BPD. Finally, exploratory epistatic analyses demonstrated potential interactive effects, especially regarding variations in CACNA1C and CHRNA7. Limitations: Limited sample size and risk of false-positive findings. Discussion: Our data suggest a possible role of these 3 genes in BPD. Alterations of 1 or more common brain pathways (e.g., neurodevelopment and neuroplasticity, calcium signaling) may explain the obtained results.

M44 - Investigation of Genetic Variants Within Genes Targets of Antipsychotic Response And Their Signal Cascade In Schizophrenia And Antipsychotic Response

Background Schizophrenia (SCZ) is a devastating psychiatric disease that affects about 1% of the population and ranks among the top 10 causes of disability worldwide. Although environmental factors can play a relevant role in the development of SCZ, evidences from family, twin, and adoption studies suggest a strong genetic component in the etiology of the disease. Similarly, a genetic contribution for antipsychotic outcome has been suggested. In the present study we investigated the associations among two distinct groups of single nucleotide polymorphisms (SNPs) within 1) genes coding for molecular targets of antipsychotic drugs and 2) genes whose products were involved with the signal transduction of the primary molecular targets. Methods Two independent samples were investigated in this study. A Korean sample of 176 in-patients and 326 healthy controls and an Italian sample of 83 patients and 195 healthy controls. A total of 100 SNPs within 18 genes were analyzed in the two samples. We investigated 1) differences among genotypic and allelic frequencies in patients with SCZ compared with healthy control subjects and 2) possible influence of the SNPs under investigation on clinical improvement, as measured with the PANSS total scale in SCZ patients. Results In the Italian sample, rs12668837 within NCAPG2 and rs7439 within PKDCC showed a different allelic distribution between cases and controls. In the pharmacogenetic analysis, variants within CHRNA7, MAPK1 genes (which coding for antipsychotic targets) and variants within PLA2G4A, ESYT2 and HOMER1 genes (which are involved in the antipsychotic targets signal transduction) showed trends of association with antipsychotic response as measured by PANSS scale. Discussion Overall, our data suggest a possible role of these two groups of genes in both SCZ pathophysiology and antipsychotic response. A limited sample size and the consequent risk of false positive findings should be carefully taken into consideration when evaluating these results.

T31 - Genes Involved In Neurodevelopment, Neuroplasticity And Bipolar Disorder: Cacna1c, Chrna1 And MAPK1

Background Bipolar Disorder (BPD) is a common and severe mental disorder. The involvement of genetic factors in the pathophysiology of BPD is well known. In the present study we tested the association of several SNPs within three strong candidate genes, CACNA1C, CHRNA7 and MAPK1, with BPD. These genes are involved in monoamines-related pathways as well as in dendrites development, neuronal survival, synaptic plasticity and memory/learning. Methods One hundred and thirty-two (132) subjects diagnosed with BPD and 326 healthy controls of Korean ancestry were genotyped for 40 SNPs within CACNA1C, CHRNA17 and MAPK1. Distribution of alleles and block of haplotypes within each gene were compared in cases and controls. Interactions between variants in different loci were also tested. Results Significant differences in the distribution of alleles between the cases and controls where detected for rs1016388 within CACNA1C, rs1514250, rs2337980, rs6494223, rs3826029 and rs4779565 within CHRNA7 and rs8136867 within MAPK1. Haplotype analyses also confirmed an involvement of variations within these genes in BPD. Finally, exploratory epistatic analyses demonstrated potential interactive effects, especially regarding variations in CACNA1C and CHRNA7. Discussion Overall, our data suggest a possible role of these three genes in BPD. Alterations of one or more common brain pathways (e.g. neurodevelopment and neuroplasticity, calcium signaling) may explain the obtained results. However, a limited sample size and the consequential risk of false positive findings should be taken into consideration when evaluating this data.

Bevacizumab as first-line treatment of ovarian cancer: strengths and weaknesses of subgroup analyses

Bevacizumab is approved as first-line treatment for ovarian cancer, in combination with carboplatin-paclitaxel, in patients with FIGO IIIb or IV disease, and as maintenance therapy. The results of subgroup analyses of data from the ICON7 study have resulted in bevacizumab use being restricted to “high-risk” patients in several countries. While a goal of obtaining as much information as possible from clinical trial data is understandable, there are also a number of limitations associated with subgroup analyses. Interpretation can be limited by the multiplicity of statistical tests (increasing the risk of false positive findings) and by low statistical power (increasing the chance of false negative results). In addition, the credibility of subgroup analyses is improved if they are restricted to the primary study outcome and limited to a small number of predefined patient subgroups. Overall, subgroup findings should be considered exploratory and hypothesis-generating. The subgroup analysis in ICON7 had a number of limitations, including post hoc definition of “high-“ and “lowrisk” groups, and questionable applicability of these definitions to clinical practice. Use of residual disease as a determinant of risk status is also problematic. Excessive emphasis on the role of subgroup analyses may lead to misunderstanding of the true results generated by the overall trial data, and support the incorrect selection of patients to be treated with the new or experimental therapy. Caution should be used in translating results of subgroup analysis to clinical practice guidelines.

Is There a Neuroanatomical Basis for the Vulnerability to Suicide?

Is there a neuroanatomical basis for the vulnerability to suicide? Kees van Heeringen MD PhD Unit for Suicide Research Ghent University, Belgium 1. Objectives Suicidal behaviour is the consequence of the interaction between stressors and a diathesis or vulnerability. Evidence is accumulating that changes in the central nervous system contribute to this vulnerability. A substantial number of imaging studies in suicide attempters have been published, but most studies are characterized by small sample sizes and increased risk of false positive findings. Therefore, the current study aimed at a systematic review and meta-analysis of published study in order to describe consistently identified disturbances in brain structure and, or, functions. 2. Methods Systematic review and meta-analysis of imaging studies of attempted suicide patients, affective controls and healthy volunteers, including structural and functional MRI studies and molecular imaging studies. 3. Results A reduced prefrontal perfusion or metabolism, a blunted increase in activation when challenged, and impairment of the prefrontal serotonergic system in association with a history of suicide attempts is shown in molecular imaging studies. Recent structural and functional imaging studies show changes in cortical and subcortical areas and their connections. Meta-analyses revealed structural deficits and functional changes in association with a history of suicidal behaviour. Structural findings included reduced volumes of the rectal gyrus, superior temporal gyrus and caudate nucleus. Functional differences between study groups included an increased reactivity of the anterior and posterior cingulate cortices to negatively valenced emotional stimuli. A number of methodological issues hamper the interpretation of findings. Nevertheless, there is increasing evidence of the involvement of a serotonin-mediated network in suicidal behaviour. The involvement of this network in decision-making, and particularly the prediction of reward and punshment, has been shown previously in healthy individuals. 4. Conclusions A diathesis to suicidal behaviour appears to be associated with changes in biochemical, functional and structural brain characteristics, which point at the involvement of a serotonin-mediated decision-making network in the development of suicidal behaviour.