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Cited by 20Connective tissue disorders researchChild and Adolescent Psychosocial and Emotional DevelopmentAnxiety, Depression, Psychometrics, Treatment, Cognitive Processes

Variant connective tissue (joint hypermobility) and its relevance to depression and anxiety in adolescents: a cohort-based case–control study

Open access
Eccles, Jessica A, Quadt, Lisa, McCarthy, Hannah, Davies, Kevin A, Bond, Rod, David, Anthony S, Harrison, Neil A, Critchley, Hugo D·2022·BMJ Open
DOI 10.1136/bmjopen-2022-066130PMC PMC9723902
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Abstract

Objective: To test whether variant connective tissue structure, as indicated by the presence of joint hypermobility, poses a developmental risk for mood disorders in adolescence. Design: Cohort-based case–control study. Setting: Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) were interrogated. Participants: 6105 children of the ALSPAC cohort at age 14 years old, of whom 3803 also were assessed when aged 18 years. Main outcome measures: In a risk analysis, we examined the relationship between generalised joint hypermobility (GJH) at age 14 years with psychiatric symptoms at age 18 years. In an association analysis, we examined the relationship between presence of symptomatic joint hypermobility syndrome (JHS) and International Classification of Diseases-10 indication of depression and anxiety (Clinical Interview Schedule Revised (CIS-R), Anxiety Sensitivity Index) at age 18 years. Results: GJH was more common in females (n=856, 28%) compared with males (n=319, 11%; OR: 3.20 (95% CI: 2.78 to 3.68); p<0.001). In males, GJH at age 14 years was associated with depression at 18 years (OR: 2.10 (95% CI: 1.17 to 3.76); p=0.013). An index of basal physiological arousal, elevated resting heart rate, mediated this effect. Across genders, the diagnosis of JHS at age 18 years was associated with the presence of depressive disorder (adjusted OR: 3.53 (95% CI: 1.67 to 7.40); p=0.001), anxiety disorder (adjusted OR: 3.14 (95% CI: 1.52 to 6.46); p=0.002), level of anxiety (B=8.08,t(3278)=3.95; p<0.001) and degree of psychiatric symptomatology (B=5.89,t(3442)=5.50; p<0.001). Conclusions: Variant collagen, indexed by joint hypermobility, is linked to the emergence of depression and anxiety in adolescence, an effect mediated by autonomic factors in males. Recognition of this association may motivate further evaluation, screening and interventions to mitigate development of psychiatric disorders and improve health outcomes.

AI snapshot

Written from the paper’s full text.

TL;DR

In the ALSPAC cohort, generalised joint hypermobility (GJH) at age 14 was associated with later depression at age 18, particularly in males, and symptomatic joint hypermobility syndrome (JHS) at age 18 was associated with concurrent depression and anxiety. Resting heart rate mediated the male GJH–depression relationship.

Key findings

  • GJH at age 14 was more common in females (n=856, 28%) than males (n=319, 11%; OR 3.20, 95% CI 2.78 to 3.68; p<0.001).
  • Across the whole group, GJH at age 14 was associated with depression at age 18 (OR 1.70, 95% CI 1.31 to 2.22; p=0.001); in males the association was significant (OR 2.10, 95% CI 1.17 to 3.76; p=0.013), and heart rate at age 14 mediated this effect (indirect effect b=1.05, 95% CI 1.011 to 1.125). GJH at age 14 was not associated with anxiety at age 18.
  • JHS at age 18 was associated with depressive disorder (adjusted OR 3.53, 95% CI 1.67 to 7.40; p=0.001), anxiety disorder (adjusted OR 3.14, 95% CI 1.52 to 6.46; p=0.002), anxiety sensitivity (B=8.08, t(3278)=3.95; p<0.001), and total psychiatric symptomatology (B=5.89, t(3442)=5.50; p<0.001).

Methods

  • Cohort-based case–control study using the Avon Longitudinal Study of Parents and Children (ALSPAC). The risk set included 6105 adolescents with complete joint hypermobility assessment at age 14; 3803 completed depression/anxiety assessments at age 18. The association sample included 4390 adolescents who completed both joint hypermobility and CIS-R at age 18, with a subset of 3443 also assessed for chronic widespread pain.
  • GJH was measured by the modified Beighton 9-point score (cut-off ≥4); JHS was operationalised as GJH plus chronic widespread pain at age 18. Depression and anxiety were measured at age 18 using the computerised CIS-R and the Anxiety Sensitivity Index.
  • Analyses used logistic regression for odds ratios, linear regression for severity scores, and mediation analysis with heart rate as mediator in males using probit regression with full information maximum likelihood and bootstrapping (n=2000), controlling for age and BMI.

Limitations

  • Stated: ALSPAC measurement instruments limited the study; classification of joint hypermobility and symptomatic JHS remains debated; the Beighton scale’s utility and cut-offs in children/adolescents are questioned; the CIS-R does not control or test for other psychiatric conditions and is only an approximation for depression/anxiety; neurodevelopmental variables were based on parent reports at age 9 and were outside the scope of this work.
  • Stated: JHS was rare in males (n=3), so JHS analyses were not powered to be undertaken separately by sex.
  • Evident from the text: the observational cohort design cannot establish causality, and available data points were limited by the original cohort study design, with missing data addressed through full information maximum likelihood estimation.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1136/bmjopen-2022-066130

Cites

46 of 46 references verified0 citation errors · 0 not checkable

Statistics

10 tests recomputed · 0 with the reported and recomputed p on opposite sides of .05

Claims the paper makes

26 of 49 cited sources checked · 16 supported · 0 flagged · accuracy not yet measured

  • Findingcitation

    Of those assessed at 14 years, 1175 (19%) had generalised joint hypermobility (GJH).

    “Of those assessed at 14 years, 1175 (19%) had GJH as reported elsewhere.9”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [9] source

      The Results report generalized joint laxity in 19.2% of 6,022 children assessed at a mean age of 13.8 years, supporting the rounded 19% at age 14. But they give 1,156 affected children, not 1,175; the exact count is unsupported. The indexed copy provides no page number for this passage. (LLM, conf=0.91)

      Experimental — accuracy not yet measured
  • Premisecitation

    GJH has been robustly associated with psychiatric conditions and psychological symptoms.

    “GJH has been robustly associated with psychiatric conditions and psychological symptoms,10”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [10] Sharp, 2021, Connecting brain and body: Transdiagnostic relevance of connective tissue variants to neuropsychiatric symptom expression, World J Psychiatry source
  • Premisecitation

    Reported co-occurrences are potentially skewed by underdiagnosis of neurodivergence in females.

    “Importantly, however reported co-occurrences are potentially skewed by underdiagnosis of neurodivergence in females.45”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [45] source

      In “Males and females may require partly different criteria in defining ‘having’ ASD” (page unavailable), the review suggests that under-identification of autistic females with typical intellectual functioning may explain the reported higher prevalence of co-occurring intellectual disability among diagnosed females. This supports a possible skew in that specific co-occurrence, but the claim extends it to reported co-occurrences and neurodivergence generally, which the passage does not establish. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Neurodivergence increases the likelihood of clinical anxiety and depression.

    “Neurodivergence also increases the likelihood of clinical anxiety and depression,46 and it is plausible that this mechanism may account for the observed association between GJH at 14 years and high rates of depression at age 18 years in males.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [46] source

      The “Burden of adult ADHD” section says ADHD is associated with a higher risk of developing mood and anxiety disorders, including major depressive disorder. The source addresses ADHD specifically, not neurodivergence generally, so it does not support extending that risk to all forms of neurodivergence. Page numbers were not provided in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Adolescents with PoTS have greater resting heart rates than peers without PoTS.

    “Adolescents with PoTS have greater resting heart rates than peers without PoTS.27”
    Quote in the paperSubstantial claim1 of 1 sources checked
  • Classified as probably not a substantial claim. 47
  • May combine two claims. 25

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In that cross-sectional case-control study, 16% of children in the comparison group had GJH.

    “In contrast, 16% of children in the comparison group had GJH, and age was found to be a risk factor, whereas sex, severity and type of anxiety disorder and attention deficit hyperactivity disorder (ADHD) were not predictive of GJH.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [29] Parvaneh J , Modaress S , Zahed G . Prevalence of generalized joint hypermobility in children with anxiety disorders. BMC Musculoskeletal Disorders 2020;21. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    ALSPAC is a birth cohort of 14,062 live births from women living in the former Avon County, southwest England, with expected delivery dates between April 1991 and December 1992.

    “The ALSPAC birth cohort follows children of 14 062 live births from women living in (the former) Avon County, a geographically defined region in southwest England, with expected dates of delivery between April 1991 and December 1992 (http://www.bristol.ac.uk/alspac).30”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [30] source

      In “Who is in the cohort?”, the paper confirms the Avon-area residence criterion and estimated delivery dates of 1 April 1991 to 31 December 1992. Its “ALSPAC recruitment rates” section reports 14,062 live-born children from pregnancies recruited antenatally, but says later recruitment brought the enrolled total to 14,775 live-born children. The claim does not qualify 14,062 as the initial recruitment group. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Adolescents with PoTS have greater resting heart rates than those without PoTS.

    “Adolescents with PoTS have greater resting heart rates than those without PoTS.27”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [27] source

      The Results (page not provided) report higher supine resting heart rates in patients than controls: 75±14 versus 68±14 bpm. However, the patient group comprised children and adolescents referred for suspected POTS or orthostatic intolerance, not specifically adolescents diagnosed with POTS. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Neuroimaging studies of individuals with joint hypermobility have identified structural and functional differences within brain regions implicated in emotional arousal, reactivity and feelings, notably the amygdala and insula.

    “Correspondingly, neuroimaging studies of individuals with joint hypermobility have identified structural and functional differences within brain regions implicated in emotional arousal, reactivity and feelings, notably amygdala16 and insula.17”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [16] source
    • cites [17] Mallorquí-Bagué, 2014, Neuroimaging and psychophysiological investigation of the link between anxiety, enhanced affective reactivity and interoception in people with joint hypermobility, Front Psychol source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Joint hypermobility is linked to autonomic problems (dysautonomia).

    “Joint hypermobility is also linked to autonomic problems (dysautonomia),25”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] Celletti, 2017, Orthostatic intolerance and postural orthostatic tachycardia syndrome in joint hypermobility Syndrome/Ehlers-Danlos syndrome, hypermobility type: Neurovegetative dysregulation or autonomic failure?, Biomed Res Int source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    A recent cross-sectional case-control study compared 93 children aged 8 to 15 years with anxiety disorders with 100 age- and sex-matched children without anxiety disorders, and found that according to Beighton criteria, 52.7% of children with anxiety disorders had GJH.

    “However, a recent cross-sectional case–control study compared 93 children between the ages of 8 and 15 years with anxiety disorders with 100 age-matched and sex-matched children without anxiety disorders, and found that according to Beighton criteria, 52.7% of children with anxiety disorders had GJH.29”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [29] Parvaneh J , Modaress S , Zahed G . Prevalence of generalized joint hypermobility in children with anxiety disorders. BMC Musculoskeletal Disorders 2020;21. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In that cross-sectional case-control study, age was found to be a risk factor for GJH.

    “In contrast, 16% of children in the comparison group had GJH, and age was found to be a risk factor, whereas sex, severity and type of anxiety disorder and attention deficit hyperactivity disorder (ADHD) were not predictive of GJH.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [29] Parvaneh J , Modaress S , Zahed G . Prevalence of generalized joint hypermobility in children with anxiety disorders. BMC Musculoskeletal Disorders 2020;21. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Higher resting heart rate predicts subsequent psychological symptoms in a large longitudinal cohort study.

    “Differences in cardiovascular autonomic activity (eg, heart rate) between individuals with and without psychiatric conditions have been observed, where higher resting heart rate predicts subsequent psychological symptoms in a large longitudinal cohort study.18 19”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [18] Kendler, 2021, The causal nature of the association between resting pulse in late adolescence and risk for internalizing and externalizing disorders: a co-relative analysis in a national male Swedish sample, Psychol Med source

      The Methods (page unavailable) describe a large longitudinal cohort of 369,301 Swedish males whose resting pulse was measured before later outcomes were assessed. The Discussion (page unavailable) reports that higher pulse was associated with later major depression and anxiety disorders, but lower pulse was associated with externalizing outcomes. Thus, the claim is supported for those internalizing disorders, not for psychological symptoms generally. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [19] Latvala, 2016, Association of resting heart rate and blood pressure in late adolescence with subsequent mental disorders: a longitudinal population study of more than 1 million men in Sweden, JAMA Psychiatry source

      The Discussion reports that, in a large longitudinal cohort of men, higher resting heart rate in late adolescence was associated with later OCD, schizophrenia, and anxiety disorder diagnoses. The claim broadens those specific diagnoses to “psychological symptoms,” which the study did not measure as stated; it also omits the finding that lower heart rate was associated with some other psychiatric outcomes. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    GJH is defined as the presence of ≥4 hypermobile joints, in common with other investigators.

    “In common with other investigators, we used a cut-off point of ≥4 hypermobile joints as a dichotomised definition of the presence of GJH.9”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In that cross-sectional case-control study, sex, severity and type of anxiety disorder and ADHD were not predictive of GJH.

    “In contrast, 16% of children in the comparison group had GJH, and age was found to be a risk factor, whereas sex, severity and type of anxiety disorder and attention deficit hyperactivity disorder (ADHD) were not predictive of GJH.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [29] Parvaneh J , Modaress S , Zahed G . Prevalence of generalized joint hypermobility in children with anxiety disorders. BMC Musculoskeletal Disorders 2020;21. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Symptoms of depression are associated with altered autonomic activity, such as increases in electrodermal activity, skin temperature and respiratory frequency, and decreased heart rate variability.

    “Symptoms of depression are associated with altered autonomic activity,20 21 such as increases in electrodermal activity,22 skin temperature and respiratory frequency,23 and decreased heart rate variability.24”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [20] source

      In “Perturbation of Internal Visceral State” (page unavailable), the paper links bodily-state regulation to autonomic control and suggests that clinical depression may involve aberrant reactions to visceral perturbation. That supports a broad connection, but the paper frames the depression link as a possibility rather than establishing the stated association. The specific physiological measures have separate citations in the citing sentence and are not attributed to this source. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [21] Ranfaing, 2021, Attention orientation to pleasantness and depressive symptomatology predict autonomic reactivity, Cogn Emot source
    • cites [22] Branković, 2008, System identification of skin conductance response in depression - an attempt to probe the neurochemistry of limbic system, Psychiatr Danub

  • Classified as probably not a substantial claim.

    Premisecitation

    A nationwide population-wide cohort study demonstrates association between hypermobility and a variety of psychiatric disorders.

    “A nationwide population-wide cohort study demonstrates association between hypermobility and a variety of psychiatric disorders.12”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Cederlöf, 2016, Nationwide population-based cohort study of psychiatric disorders in individuals with Ehlers-Danlos syndrome or hypermobility syndrome and their siblings, BMC Psychiatry source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A Swedish cohort study demonstrated that adolescent males with higher basal heart rate are more likely to develop subsequent psychopathology, notably anxiety disorders.

    “Interestingly, a Swedish cohort study also demonstrated that adolescent males with higher basal heart rate are more likely to develop subsequent psychopathology, notably anxiety disorders.19”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Latvala, 2016, Association of resting heart rate and blood pressure in late adolescence with subsequent mental disorders: a longitudinal population study of more than 1 million men in Sweden, JAMA Psychiatry source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Such an association between GJH and anxiety is widely reported in adults.

    “This observation is striking as such an association is widely reported in adults.10 13 42”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [10] Sharp, 2021, Connecting brain and body: Transdiagnostic relevance of connective tissue variants to neuropsychiatric symptom expression, World J Psychiatry source
    • cites [13] source
    • cites [42] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In adults, the link between variant connective tissue structure (indexed by joint hypermobility) and affective psychopathology is largely established and reinforced by convergent evidence from domestic dogs.

    “In adults, the link between variant connective tissue structure (indexed by joint hypermobility) and affective psychopathology is largely established13 and, interestingly, reinforced by convergent evidence from domestic dogs.41”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [13] source
    • cites [41] Bowen, 2019, First evidence for an association between joint hypermobility and excitability in a non-human species, the domestic dog, Sci Rep source

  • May combine two claims.

    Premisecitation

    Joint hypermobility is also associated with neurodivergence (including Fragile X syndrome, ADHD and autism), which is more commonly diagnosed in males.

    “However, despite this female preponderance, joint hypermobility is also associated with neurodivergence44 (including Fragile X syndrome, ADHD and autism), which is more commonly diagnosed in males.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [44] Csecs, 2021, Joint hypermobility links Neurodivergence to dysautonomia and pain, Front Psychiatry source

      The Discussion (page unavailable) reports that generalized joint hypermobility was more than twice as prevalent in the neurodivergent groups, including autistic participants and people with ADHD. The paper does not address Fragile X syndrome, and its sample being 62% male does not establish that neurodivergence is more commonly diagnosed in males. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Symptomatic hypermobility (hEDS/HSD/JHS) is considered to be an autosomal dominant trait with incomplete penetrance, variable expressivity and influenced by sex, since joint hypermobility is more common in females.

    “Nevertheless, symptomatic hypermobility (hEDS /HSD/JHS) is considered to be an autosomal dominant trait with incomplete penetrance, variable expressivity and influenced by sex, since joint hypermobility is more common in females.43”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [43] Castori, 2012, Ehlers-Danlos syndrome, hypermobility type: an underdiagnosed hereditary connective tissue disorder with mucocutaneous, articular, and systemic manifestations, ISRN Dermatol source

      In §4.1 (Inheritance Pattern), Castori describes JHS/EDS-HT as an autosomal dominant trait with incomplete penetrance, variable expressivity, and an influence of sex. The same section reports that females more commonly meet its diagnostic criteria, while §2 (Definition(s)) says joint hypermobility is more common in females. The paper does not address HSD, so extending the inheritance characterization to that category is not established by this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Variant connective tissue, expressed as joint hypermobility, is characteristically a familial trait.

    “Variant connective tissue, expressed as joint hypermobility, is characteristically a familial trait.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [43] Castori, 2012, Ehlers-Danlos syndrome, hypermobility type: an underdiagnosed hereditary connective tissue disorder with mucocutaneous, articular, and systemic manifestations, ISRN Dermatol source

  • May combine two claims.

    Findingown data

    In the ALSPAC cohort at age 14 years, generalised joint hypermobility (GJH) was more common in females (28%) than in males (11%), with OR 3.20 (95% CI 2.78 to 3.68), p<0.001.

    “GJH was more common in females (n=856, 28%) compared with males (n=319, 11%; OR: 3.20 (95% CI: 2.78 to 3.68); p<0.001).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Heart rate at age 14 was significantly associated with variations in exact age (months) (r(5729)=−0.32, p=0.016).

    “and was significantly associated with variations in exact age (months) (r(5729)=−0.32, p=0.016) and BMI (r(5722)=0.081, p<0.001) at assessment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Heart rate at age 14 was significantly higher in females (M=83.92, SD=11.94) than males (M=78.6, SD=11.44; t(5725)=17.18, p<0.001).

    “Heart rate was significantly higher in females (M=83.92, SD=11.94) than males (M=78.6, SD=11.44; t(5725)=17.18, p<0.001)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Heart rate at age 14 was significantly associated with BMI (r(5722)=0.081, p<0.001).

    “and was significantly associated with variations in exact age (months) (r(5729)=−0.32, p=0.016) and BMI (r(5722)=0.081, p<0.001) at assessment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Symptomatic joint hypermobility (JHS), operationalised as the presence of GJH and CWP, was associated with both anxiety and depression in female adolescents and across the whole group when adjusted for sex.

    “However, symptomatic joint hypermobility (JHS) operationalised here as the presence of GJH and CWP was associated with both anxiety and depression in female adolescents and across the whole group when adjusted for sex.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Across the whole group, JHS was significantly associated with depression at age 18 years, and this association remained significant when adjusted for sex.

    “Across the whole group, JHS was significantly associated with depression at age 18 years (figure 5 shows ORs for this effect, which remained significant when adjusted for sex).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    JHS was significantly associated with any anxiety disorder at age 18 years, and this relationship remained significant when adjusted for sex.

    “JHS was significantly associated with any anxiety disorder at age 18 years, a relationship that remained significant when adjusted for sex. ORs are displayed in figure 5.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both GJH and heart rate at age 14 years were significantly associated with depression at age 18 years.

    “Both GJH and heart rate (at age 14 years) were significantly associated with depression (at age 18 years).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    JHS diagnosis is typically based on the revised Brighton criteria, requiring a combination of major and minor criteria, comprising GJH with significant musculoskeletal and/or connective tissue symptoms.

    “JHS diagnosis is typically based on the revised Brighton criteria,33 and requires a combination of major and minor criteria, comprising GJH in combination with significant musculoskeletal and/or connective tissue symptoms.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Grahame, 2000, The revised (Brighton 1998) criteria for the diagnosis of benign joint hypermobility syndrome (BJHS), J Rheumatol

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    CIS-R is a standardised tool for measuring depression and anxiety in community samples, including this cohort.

    “CIS-R is a standardised tool for measuring depression and anxiety in community samples,32 including this cohort.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Of the risk set, 5731 adolescents also had heart rate data recorded at age 14.

    “Of this risk set, 5731 adolescents also had heart rate data recorded at age 14.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Joint hypermobility is more common in females and declines with age.

    “Joint hypermobility is typically assessed using the Beighton scale,6 and is more common in females, declining with age.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] source

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductcitation

    GJH was measured by trained assessors using the modified Beighton 9-point scoring system at ages 14 and 18.

    “ALSPAC participants underwent measurement of GJH in a dedicated research clinic, by trained assessors using the modified Beighton 9-point scoring system6 at two time points; age 14 years and age 18 years.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] source

  • Classified as probably not a substantial claim.

    Premisecitation

    Adults with GJH are over-represented among patients expressing common mental disorders, namely depression, anxiety and panic.

    “where adults with GJH are over-represented among patients expressing common mental disorders; that is, depression, anxiety and panic.11”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Bulbena, 2017, Psychiatric and psychological aspects in the Ehlers-Danlos syndromes, Am J Med Genet C Semin Med Genet source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Generalised joint hypermobility (GJH) is a characteristic marker of hereditary disorders of connective tissue, compromising a matrix of proteins including collagens, elastins, fibrillins and tenascins.

    “Generalised joint hypermobility (GJH) is a characteristic marker of hereditary disorders of connective tissue, compromising a matrix of proteins that includes collagens, elastins, fibrillins and tenascins.5”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Baeza-Velasco, 2015, Joint hypermobility and the heritable disorders of connective tissue: clinical and empirical evidence of links with psychiatry, Gen Hosp Psychiatry source

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Of these, 3803 adolescents completed assessments for depression and anxiety (CIS-R) at age 18.

    “Of these, 3803 adolescents completed assessments for depression and anxiety (Clinical Interview Schedule Revised; CIS-R)32 aged 18 years.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The predictor model risk set included 6105 adolescents who underwent a complete joint hypermobility assessment at age 14.

    “The ‘risk set’ for the predictor model included 6105 adolescents who underwent a complete joint hypermobility assessment in a clinical setting as 14 years old adolescents.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The CIS-R quantifies symptoms to assign ICD-10 indications of depression and anxiety disorders, but does not function to exclude other psychiatric conditions which may contribute to or influence symptoms of depression and anxiety.

    “The CIS-R quantifies symptoms to assign International Classification of Diseases-10 (ICD-10) indications of depression and anxiety disorders, but does not function to exclude other psychiatric conditions which may contribute to or influence symptoms of depression and anxiety.35 36”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [35] source
    • cites [36] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    A subset of 3443 adolescents from the association sample also completed an assessment for chronic widespread pain at age 18.

    “Finally, data from a subset of 3443 adolescents from the association sample, who also completed an assessment for chronic widespread pain (CWP) at the same 18-year time point, were additionally analysed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Clinical phenotypes including hypermobile EDS (hEDS) and hypermobility spectrum disorder (including GJH) are associated with clinically significant issues.

    “GJH itself is not necessarily a medical problem, but clinical phenotypes including hypermobile EDS (hEDS; formerly known as EDS hypermobility type/EDS type-III/joint hypermobility syndrome; JHS),7 and hypermobility spectrum disorder8 (including GJH) are associated with clinically significant issues.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] source
    • cites [8] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Available data points were limited due to the design of the original birth cohort study.

    “Available data points were limited due to the design of the original birth cohort study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Postural tachycardia syndrome (PoTS) is characterised by accelerated heart rate on standing, and other symptoms that overlap phenomenologically with anxiety.

    “often expressed as postural tachycardia syndrome (PoTS), a condition characterised by accelerated heart rate on standing, and other symptoms that overlap phenomenologically with anxiety.26”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Mathias, 2012, Postural tachycardia syndrome—current experience and concepts, Nat Rev Neurol source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Full information maximum likelihood (FIML) provides robust parameter estimates despite missing data.

    “FIML chooses parameter estimates that maximise this likelihood function based on complete cases, thereby providing robust parameter estimates, despite missing data.40”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] source

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The association sample included 4390 adolescents who completed assessments for both joint hypermobility and the CIS-R at age 18.

    “The second (association) sample included the 4390 adolescents who completed assessments for both joint hypermobility and the CIS-R aged 18 years.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Mediation analyses were controlled for mean-centred age at assessment and body mass index (BMI).

    “Mediation analyses were controlled for mean-centred age at assessment and body mass index (BMI), as both were associated with the potential mediator (heart rate).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Because individual age in months varied, association tests were performed to see if age was a significant variable of interest.

    “As per ALSPAC dataset, these were broad time points and individual age in months varied, and therefore association tests were performed to see if age was a significant variable of interest.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    JHS was operationalised as meeting two major criteria: the presence of GJH and concomitant CWP, because not all minor criteria were recorded in the ALSPAC cohort at age 18.

    “Not all minor criteria were recorded in the ALSPAC cohort at age 18 years, thus JHS was operationalised as meeting two major criteria: the presence of GJH and concomitant CWP.34”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The analysis of JHS and depression was not powered to be undertaken separately in males due to low levels of JHS in males (n=3).

    “Given the low levels of JHS in males (n=3), this analysis was not powered to be undertaken separately but remained significant for females (figure 5).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    This study was limited by the measurement instruments used in the ALSPAC cohort study.

    “This study was limited by the measurement instruments used in the ALSPAC cohort study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    The ALSPAC dataset includes variables for neurodevelopmental conditions like autism and ADHD, but these are based on parent reports at age 9 years of the child and were outside of the scope of this work.

    “The ALSPAC dataset includes variables for neurodevelopmental conditions like autism and ADHD, however, these are based on parent reports at age 9 years of the child and were outside of the scope of this work.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The CIS-R is a well-established tool to find robust indications of depression and anxiety, but it does not control or test for other psychiatric conditions that may influence depressive and anxiety symptomatology.

    “While the CIS-R is a well-established tool to find robust indications of depression and anxiety, it does not control or test for other psychiatric conditions that may influence depressive and anxiety symptomatology.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Although the Beighton Scale remains the most widely used approach for measuring hypermobility, there remain considerable questions about its utility, particularly in children and adolescents, and cut-offs vary widely.

    “Although the Beighton Scale remains the most widely used approach for measuring hypermobility, there remains considerable questions about its utility, particularly in children and adolescents,48 and cut-offs vary widely.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Simmonds, 2017, Generalized joint hypermobility: a timely population study and proposal for Beighton cut-offs, Rheumatology source

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationnone given

    The contribution of underlying variant connective tissue structure is likely to be complex and involves interacting autonomic, psychological and physiological factors.

    “However, the contribution of underlying variant connective tissue structure is likely to be complex and involves interacting autonomic, psychological and physiological factors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Hypermobility is associated with dysautonomia, typically PoTS, symptoms of which have phenomenological overlap with anxiety.

    “Hypermobility is associated with dysautonomia,47 typically PoTS, symptoms of which have phenomenological overlap with anxiety.26”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [47] source
    • cites [26] Mathias, 2012, Postural tachycardia syndrome—current experience and concepts, Nat Rev Neurol source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    One possible explanation for the pattern of results is that higher rates of anxiety and depression in females reflect susceptibility and perhaps exposure to a wider range of risk factors, which obscures an association with GJH apparent in males.

    “One possible explanation for this pattern of results is that the higher rates of anxiety and depression in females reflect susceptibility and perhaps exposure to a wider range of risk factors, which obscures an association with GJH apparent in males.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    The CIS-R is only an approximation for an indication of the presence of depression and anxiety, although a tried and tested one.

    “It is therefore only an approximation for an indication of the presence of depression and anxiety, although a tried and tested one.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The categorisation and classification of joint hypermobility and symptomatic joint hypermobility remains the subject of substantial debate.

    “The categorisation and classification of joint hypermobility and symptomatic joint hypermobility remains the subject of substantial debate.8”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] source
55 of 55

  • The paper relies on this without support.

    Adolescence is a critical time in psychological and physical development.

    “Adolescence is a critical time in psychological and physical development.”

  • The paper relies on this without support.

    Joint hypermobility is more common in females.

    “Since joint hypermobility is more common in females, analyses for males and females were performed separately.”

  • The paper relies on this without support.

    Heart rate at age 14 years is a valid index of basal autonomic physiology.

    “We also show a mediating effect of basal autonomic physiology (indexed by heart rate) on this relationship.”

  • The paper relies on this without support.

    The mediation analysis's causal interpretation is valid (no unmeasured confounding between GJH, heart rate, and depression).

    “The mediation analysis showed that the relationship between GJH and depression was mediated by heart rate (figure 3).”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Anxiety scores are increased in adolescents and young adults with asymptomatic GJH compared with peers without GJH.

    “Anxiety scores in adolescents and young adults with GJH without complaints were increased compared to peers without GJH.28,41,54,56”

    From Role of Anxiety in Individuals with Generalized Joint Hypermobility: A Systematic Review (2025) · cites this paper as [41]

    The Discussion (page unavailable) explicitly reports no longitudinal association between GJH alone and anxiety. The elevated anxiety sensitivity scores in the Results (Association set analysis; page unavailable) were found in adolescents with joint hypermobility syndrome—GJH with chronic widespread pain—not in those with GJH without complaints. (LLM, conf=0.88)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Normal to mild social anxiety is present in adolescents and young adults with asymptomatic GJH.

    “Normal to mild social anxiety was present.28,41,54”

    From Role of Anxiety in Individuals with Generalized Joint Hypermobility: A Systematic Review (2025) · cites this paper as [41]

    The Methods (Outcomes) include social phobia within a broad measure of any anxiety disorder, and the Results (Risk set analysis, Table 2) report anxiety outcomes for adolescents with GJH. The paper does not report social-anxiety severity as normal to mild, or a separate result for asymptomatic GJH; the Discussion says GJH alone was not longitudinally associated with anxiety. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Statistics that don’t add up

Each reported p-value recomputed from its test statistic and degrees of freedom.

  • Inconsistent p-value: r(5729)=−0.32, p = .016

    Minor

    The paper reports p = .016 here; recomputing from the test statistic and its degrees of freedom gives p < .001 (two-tailed). The check cannot tell whether the statistic or the p-value is the misprint.

    Reported p = .016 · recomputed p < .001

1 of 1

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Doesn’t add upr(5729) = -0.32reported p = .016 · recomputed p < .001

    “r(5729)=−0.32, p = .016”

  • ConsistentF(2, 3802) = 3.73reported p = .024 · recomputed p = .024

    “F(2,3802)=3.73, p = .024”

  • Consistentt(5725) = 17.18reported p < .001 · recomputed p < .001

    “t(5725)=17.18, p < .001”

  • Consistentr(5722) = 0.081reported p < .001 · recomputed p < .001

    “r(5722)=0.081, p < .001”

  • Consistentt(3442) = 5.5reported p < .001 · recomputed p < .001

    “t(3442)=5.50, p < .001”

  • Consistentt(3441) = 4.73reported p < .001 · recomputed p < .001

    “t(3441)=4.73, p < .001”

  • Consistentt(1992) = 4.4reported p < .001 · recomputed p < .001

    “t(1992)=4.40, p < .001”

  • Consistentt(3278) = 3.95reported p < .001 · recomputed p < .001

    “t(3278)=3.95, p < .001”

  • Consistentt(3278) = 3.28reported p = .001 · recomputed p = .001

    “t(3278)=3.28, p = .001”

  • Consistentt(1907) = -3.1reported p = .002 · recomputed p = .002

    “t(1907)=−3.10, p = .002”

10 of 10

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Male depression result has a significant p-value but a confidence interval crossing one

    Major

    The reported 95% confidence interval for the male odds ratio includes 1, whereas its reported p-value is below 0.05. Those two indicators disagree about whether this result is statistically significant.

1 of 1

Cites

Flagged first, then by citations

1 of the 47 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Enders CK . Applied missing data analysis. New York, NY, US: Guilford Press, 2010.

Cited by

Sorted by citations

Related

Authors
Eccles, J. A., Quadt, L., McCarthy, H., Davies, K. A., Bond, R., David, A. S., Harrison, N. A., & Critchley, H. D.
Affiliations
  • Brighton and Sussex Medical School (GB)
  • University of Sussex (GB)
  • University College London (GB)
Corresponding author
Eccles, Jessica A
ORCID
Venue
BMJ Open
Publisher
BMJ
Published
2022-11
Volume
12
Issue
12
Pages
e066130
ISSN
2044-6055 (ISSN-L)
DOI
10.1136/bmjopen-2022-066130
PMC
PMC9723902
OpenAlex
W4310550953
Cited by
20
References
47
Citations by year
2026: 7 · 2025: 5 · 2024: 5 · 2023: 3
FWCI
1.75
Type
journal article
Language
en
Open access
Licence
Locations
  • BMJ Open (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • Sussex Research Online (University of Sussex) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
Funders
  • Medical Research Council (MR/K002643/1)
  • MQ: Transforming Mental Health ((MQF 17/19))
  • Versus Arthritis (MQF 17/19)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
  • Social Sciences › Psychology › Clinical Psychology › Child and Adolescent Psychosocial and Emotional Development
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
Keywords
joint hypermobility, connective tissue, depression, anxiety, adolescents, mood disorders, joint hypermobility syndrome, resting heart rate, autonomic nervous system, sex differences, collagen, psychiatric symptoms, anxiety sensitivity, Avon Longitudinal Study of Parents and Children, developmental risk factors, genetic risk factors
MeSH terms
Adolescent, Anxiety, Anxiety Disorders, Connective Tissue, Depression, Female, Humans, Joint Instability, Longitudinal Studies, Male, Case-Control Studies

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-13.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-13.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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