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• Medical intervention appears to reduce the risk of suicide in the treatment of gender dysphoria.
  Gideon Meyerowitz-Katz
  Published on: 15 May 2024
• Two questions about potential methodological and interpretative shortcomings
  Jamie Vesterinen
  Published on: 15 May 2024
• Significantly higher suicide mortality (p=.05) without gender reassignment should not be dismissed
  Donald Paul Sullins
  Published on: 20 March 2024
• Methods and results do not support conclusions of Ruuska et al.
  Carl Streed, Kellan Baker, Howard Cabral, Emily Sisson, Caroline Davidge-Pitts, Johanna Olson-Kennedy and Madeline Deutsch
  Published on: 20 March 2024

• Published on: 15 May 2024

  Medical intervention appears to reduce the risk of suicide in the treatment of gender dysphoria.

  • Gideon Meyerowitz-Katz, Epidemiologist School of Health and Society, University of Wollongong

  The authors present a retrospective cohort study of mostly adults who were referred to clinics in Finland for the treatment of gender dysphoria. However, one of the most important findings in this paper seems to have been missed in the discussion section.

  The authors report that suicide risk was not statistically different between people referred for treatment and a matched cohort, with a hazard ratio of 1.8 (0.6-4.8) for people referred for gender dysphoria when compared to the control in the fully adjusted model (Table 3). However, the authors also conducted this analysis using only people who had accessed gender-affirming medical interventions (categorized as "Hormonal or surgical gender reassignment interventions" in Table 1) and those who hadn't (GR+ and GR-). In many ways, this is the more important analysis, as it addresses the question of medical treatment rather than medical referral.

  The authors do note in their conclusion that there were no statistically significant differences in all-cause mortality when the data is split up into these groups, with GR- having a HR of 1.4 (0.6-3.3) and GR+ 0.7 (0.2-2). However, the results also show that the adjusted suicide mortality HRs for the GR- and GR+ groups compared to the matched control were 3.2 (1-10.2) and 0.8 (0.2-4) respectively. While the authors do not present an adjusted analysis of suicide mortality comparing these two groups directly, this implies a statistically significant associ...

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  The authors present a retrospective cohort study of mostly adults who were referred to clinics in Finland for the treatment of gender dysphoria. However, one of the most important findings in this paper seems to have been missed in the discussion section.

  The authors report that suicide risk was not statistically different between people referred for treatment and a matched cohort, with a hazard ratio of 1.8 (0.6-4.8) for people referred for gender dysphoria when compared to the control in the fully adjusted model (Table 3). However, the authors also conducted this analysis using only people who had accessed gender-affirming medical interventions (categorized as "Hormonal or surgical gender reassignment interventions" in Table 1) and those who hadn't (GR+ and GR-). In many ways, this is the more important analysis, as it addresses the question of medical treatment rather than medical referral.

  The authors do note in their conclusion that there were no statistically significant differences in all-cause mortality when the data is split up into these groups, with GR- having a HR of 1.4 (0.6-3.3) and GR+ 0.7 (0.2-2). However, the results also show that the adjusted suicide mortality HRs for the GR- and GR+ groups compared to the matched control were 3.2 (1-10.2) and 0.8 (0.2-4) respectively. While the authors do not present an adjusted analysis of suicide mortality comparing these two groups directly, this implies a statistically significant associated reduction in risk of suicide of roughly 50% for people referred to gender clinics in Finland and who had treatment when compared to those who were referred but did not access treatment.

  The authors report in their discussion that "the suicide mortality of both those who proceeded and did
  not proceed to GR did not statistically significantly differ from that of controls", indicating that presumably the p-value of the increased risk for GR- individuals was marginally above the threshold for significance (i.e. 0.051-0.0544). However, this arbitrary distinction is not useful. A more useful point is to note that the risk of suicide is substantially elevated in the GR- group, but with so few events the 95% CI reflects quite a bit of uncertainty as to the true rate. These results are consistent with everything from minimal difference in this cohort to a 10x increase.

  This result appears to undercut the authors' stated conclusion that their findings do "not support the claims that GR is necessary in order to prevent suicide". While the study has significant limitations, noted by the authors, their results do seem to support the argument that GR treatment is associated with a reduced risk of suicide for people with clinical gender dysphoria in Finland when compared to people with gender dysphoria who do not receive treatment and a matched control. These results are both uncertain due to the low sample size, but imply that gender affirming care may be linked to lower suicide rates in people with gender dysphoria while a lack of such care may increase suicides.

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  Conflict of Interest:
  None declared.

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• Published on: 15 May 2024

  Two questions about potential methodological and interpretative shortcomings

  • Jamie Vesterinen, Doctoral researcher University of Helsinki

  Hi

  I am writing here to express my concern that this paper might have some serious flaws that have apparently passed the peer review and editorial processes.

  I am a doctoral candidate in Classics and unfortunately lack sophisticated skills at statistics, but due to my background both as a doctoral researcher in another field and as a former patient in a gender identity policlinic in Finland, I do believe I am capable of raising one question about the methodology and another about the analysis of the results.

  The paper compares the all-cause mortality and suicide rates between individuals referred to gender identity clinics in Finland between 1996 and 2019 and a control group. The age limit is <23. The methodological problem that I perceive is that the paper fails to take into consideration that before 2011, minors were generally not granted referrals to gender identity clinics (see e.g. https://yle.fi/a/3-10707095 (in Finnish); https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396787/). Consequently, any mortalities among the gender-incongruent youth under 18 years old would not be associated in the statistics with referrals to gi clinics but might be included in the control group. For example, had I succeeded in my suicide attempt at the age of 15 in 2008, this would not be classified as a gender-dysphoria-linked death in this paper despite my...

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  Hi

  I am writing here to express my concern that this paper might have some serious flaws that have apparently passed the peer review and editorial processes.

  I am a doctoral candidate in Classics and unfortunately lack sophisticated skills at statistics, but due to my background both as a doctoral researcher in another field and as a former patient in a gender identity policlinic in Finland, I do believe I am capable of raising one question about the methodology and another about the analysis of the results.

  The paper compares the all-cause mortality and suicide rates between individuals referred to gender identity clinics in Finland between 1996 and 2019 and a control group. The age limit is <23. The methodological problem that I perceive is that the paper fails to take into consideration that before 2011, minors were generally not granted referrals to gender identity clinics (see e.g. https://yle.fi/a/3-10707095 (in Finnish); https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396787/). Consequently, any mortalities among the gender-incongruent youth under 18 years old would not be associated in the statistics with referrals to gi clinics but might be included in the control group. For example, had I succeeded in my suicide attempt at the age of 15 in 2008, this would not be classified as a gender-dysphoria-linked death in this paper despite my several attempts to get a referral to a gi clinic prior to attempting suicide. This considerable limitation in the dataset is not mentioned at all in the paper.

  The problem that I perceive in the analysis of the evidence is that the authors of the paper interpret the elevated suicide mortality in the gi-referred group as a consequence of mental health problems and not of (untreated) gender dysphoria. They draw the conclusion that gender dysphoria is not predictive of an elevated suicide risk in young gender-incongruent individuals. However, this conclusion seems to require that the authors completely reject the quite likely scenario that the mental health problems and suicide could both be a consequence of (untreated) gender dysphoria. On the other hand – as someone with no medical expertise –, I would consider it rather unexpected if suicides caused by untreated gender dysphoria did tend to occur without the presence of mental health issues such as major depression, anxiety-related conditions, eating disorders (for example, to control menstruation and body shape), or previous suicide attempts. However, this is what the authors of the paper seem to expect in the analysis.

  The conclusions drawn in the paper and the medical implications made at the end (i.e., stressing the treatment of mental health problems rather than gender dysphoria that may be causing them) are likely to be taken into consideration when the treatment options of gender-incongruent youth are evaluated and reshaped both in Finland and elsewhere. This is why I am deeply concerned that the shortcomings pointed out above have the potential of resulting in detrimental consequences for young people seeking medical assistance with gender dysphoria in the near future. I do believe that treatment should be based on research and not opinion, but it is of utmost importance that the research is of approvable quality and there can be no suspicion of bias.

  I would be most pleased if the authors, reviewers, or the editorial board would consider my concerns and, hopefully, demonstrate that they are unsubstantiated after all.

  With kind regards
  Jamie Vesterinen

  Doctoral researcher
  Doctoral Programme in History and Cultural Heritage
  University of Helsinki

  jamie.vesterinen@helsinki.fi

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  Conflict of Interest:
  None declared.

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• Published on: 20 March 2024

  Significantly higher suicide mortality (p=.05) without gender reassignment should not be dismissed

  • Donald Paul Sullins, Research Professor of Sociology The Catholic University of America and the Ruth Institute

  Ruuska et al.’s [1] analysis incorrectly concluded that medical gender reassignment (GR) did not reduce suicide mortality because they had assessed that “the suicide mortality of both those [presenting with gender dysphoria (GD)] who proceeded and did not proceed to GR did not statistically significantly differ from that of controls.” On the contrary, by conventional criteria, the suicide mortality of the non-GR group was significantly higher than controls while that of the GR group was not. Ruuska et al. [1] reported: "Adjusted HRs [hazard rates] for suicide mortality were 3.2 [for non-GR] (95% CI 1.0 to 10.2; p=0.05) and 0.8 [for GR] (95% CI 0.2 to 4.0; p=0.8), respectively." By this finding, those dysphorics who had undergone GR were no more likely to have committed suicide than were general population controls, while those who had not undergone GR were more than three times as likely to have committed suicide. The latter difference is reported with a p-value of .05 and a 95% confidence interval that does not extend below 1.0.

  By the prevailing standards of scientific inference, and in virtually any other study, such a finding would be assessed as statistically significant (or perhaps, depending on rounding error, trivially below significance), but Ruuska et al. [1] judged it not to be so. They achieved this anomaly by fiat, announcing: “In order to avoid type 1 error due to multiple testing and the large data size, the cut- off for statistical sign...

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  Ruuska et al.’s [1] analysis incorrectly concluded that medical gender reassignment (GR) did not reduce suicide mortality because they had assessed that “the suicide mortality of both those [presenting with gender dysphoria (GD)] who proceeded and did not proceed to GR did not statistically significantly differ from that of controls.” On the contrary, by conventional criteria, the suicide mortality of the non-GR group was significantly higher than controls while that of the GR group was not. Ruuska et al. [1] reported: "Adjusted HRs [hazard rates] for suicide mortality were 3.2 [for non-GR] (95% CI 1.0 to 10.2; p=0.05) and 0.8 [for GR] (95% CI 0.2 to 4.0; p=0.8), respectively." By this finding, those dysphorics who had undergone GR were no more likely to have committed suicide than were general population controls, while those who had not undergone GR were more than three times as likely to have committed suicide. The latter difference is reported with a p-value of .05 and a 95% confidence interval that does not extend below 1.0.

  By the prevailing standards of scientific inference, and in virtually any other study, such a finding would be assessed as statistically significant (or perhaps, depending on rounding error, trivially below significance), but Ruuska et al. [1] judged it not to be so. They achieved this anomaly by fiat, announcing: “In order to avoid type 1 error due to multiple testing and the large data size, the cut- off for statistical significance was set at a p<0.01” [1] rather than the usual standard of p<0.05. This is a decision is highly questionable, for two reasons. First, the size of the data analyzed is not nearly large enough to justify it: 18,726 cases (122,358 person-years). Preference for a .01 criterion usually involves data numbering in the hundreds of thousands, at least, and even then rarely precludes recognition of substantively important findings that may have a higher p-value below .05. Of the ten most recent studies using larger similar data—extractions from Finnish registers that are as large or larger than that of Ruuska et al. [1] —with numbers of cases ranging from 24,341 to 5.6 million (the entire Finnish population), or 41.9 million person-years, none rejected findings between .05 and .01 as not being statistically significant. (See Endnote 1) The most methodologically similar study of the same subject as that of Ruuska et al. [1] , Dhejne et al.’s [11] 2011 examination of the Swedish population register, also used the conventional .05 standard. None of these large-data register studies rejected as insignificant a finding with p less than .05 but greater than .01, or a 95% confidence interval that did not include nullity, except for Ruuska et al. [1] Co-authors of the Ruuska et al. [1] study also imposed a restrictive .01 standard for significance on an earlier register study of gender reassignment, [12] but did not do so for similarly-sized register studies of other topics, for example schizophrenia (17,112 cases), [13] and depression (16,842 cases). [14]

  More importantly, second, adjusting the significance criterion to reduce the prospect of one type of error inescapably imbalances or biases, by the same amount, the analysis toward the opposite error. In this case, it perversely increases the risk of the very type of error the stricter criterion is trying to avoid. This is because adopting a stricter significance criterion to reduce the risk of Type I errors due to perceived statistical significance raises, by the same amount, the risk of Type I errors due to perceived lack of statistical significance; and the inference that GR did not reduce suicide is based on perceived statistical insignificance. If the goal were not to affirm too easily substantive findings that may be due to measurement imprecision, then for conclusions that depend on similarity between groups rather than difference, the criterion for assessing true difference should be made less strict (perhaps .10), not more strict. A better practice, followed in many studies, might be to avoid unilaterally adjusting the conventional scientific standard of inference, but present findings as more or less certain with reference to that standard depending on their reported actual p-value.

  Recognition that suicide risk may be lower with GR than without it in this analysis complicates, but does not negate, Ruuska et al’s [1] substantive observation that this comparison “does not support the claims that GR is necessary in order to prevent suicide.” It complicates it because a similar previous analysis of the same register data involving two of the same authors [12] already found that, when adjusted for year of initial contact with Finland’s gender identity service, follow-up contact with psychiatric care was emphatically no different by medical gender reassignment (GR) status. In that study, the hazard ratio (HR) for those gender dysphorics who had undergone GR—3.8 (95% CI 3.6-4.1)—was virtually identical to that of those who had not done so—3.9 (95% CI 3.6-4.2). Both of these HRs differed significantly from controls but did not differ significantly from each other. Unlike Ruuska et al., [1] they provided strong support for the earlier study’s conclusion that these findings “do not suggest that medical GR interventions resolve psychiatric morbidity among people experiencing gender distress.”[12]

  This does not mean that Ruuska et al.’s observation is incorrect. There are at least two plausible explanations for the apparent contradiction of lower suicide mortality following GR despite similar high psychiatric morbidity, compared to GD registrants who did not receive GR. The first explanation reflects the time trajectory of suicide mortality. Dhejne et al. (2011), in the only other national registry study of completed suicide, observed that “survival of transsexual persons [undergoing medical gender reassignment] started to diverge from that of matched controls after about 10 years of follow-up.” [11] Up until 10 years post GR, the suicidal mortality of the Swedish registrants in the Dhejne et al. (2011) study did not differ from that of the general population controls, which is exactly what is observed, at an average follow-up of only 6.5 years, among the Finnish registrants in the Ruuska et al. [1] study. After 10 years, however, Dhejne et al. (2011) found that suicide mortality among Swedish GR recipients increased dramatically, a possibility that is not at all foreclosed for their Finnish counterparts by the findings of Ruuska et al. [1] .

  A second explanation is suggested by the fact that, unlike in many jurisdictions, in Finland only 38% of GD diagnosed persons in treatment proceeded to medical GR. This suggests the presence of assessment, screening and monitoring processes that may inhibit some of the negative consequences of psychiatric morbidity, for example by ensuring better social support or medication compliance, than may be the case in other settings.
  These two explanations are not mutually exclusive; both may be the case to some extent. Neither of them, moreover, impair in any way the main conclusion of Ruuska et al’s [1] study, that apart from attendant psychiatric morbidity, gender dysphoria in itself does not predict suicide mortality. Both also strongly support the important clinical implication of the study, that it is “of utmost importance to identify and appropriately treat mental disorders in adolescents experiencing gender dysphoria to prevent suicide.”

  Endnote 1: The studies are: Bockerman et al.’s study of opioid use and employment rates (41.9 million person-years) [2]; Silenpaa et al.’s estimation of childhood epilepsy incidence (entire population rates); [3] Vaajala et al.’s (2024) study of fear of childbirth (comparing 211,202 cases from the Finnish Birth Register); [4] Ax et al.’s (2024) study of hand surgery and sick leave (24,341 cases); [5] Valtanen et al.’s (2024) comparison of psychiatric medication use by treatment strategy (44,685 cases); [6] Raudasoja et al. (2024), examining corrective surgery after treatment of distal radial fractures (41,418 cases); [7] Terho et al’s. (2024) study of frozen embryo transfer child growth rates (35,894); [8] Tamlander et al’s (2024) analysis of implications of polygenic risk for colorectal cancer screening (453,733 cases); [9] Kolari et al. (2024), examining ADHD medication use among Finnish children (41,920 cases); [10] and Holm et al.’s (2024) study of nonaffective psychosis diagnosis, examining 49,164 persons.

  References
  1 Ruuska S-M, Tuisku K, Holttinen T, et al. All-cause and suicide mortalities among adolescents and young adults who contacted specialised gender identity services in Finland in 1996–2019: a register study. BMJ Ment Health. 2024;27:e300940.
  2 Böckerman P, Haapanen M, Hakulinen C, et al. Prescription opioid use and employment: A nationwide Finnish register study. Drug and Alcohol Dependence. 2021;227:108967.
  3 Sillanpää ML, Camfield P, Löyttyniemi E. The changing incidence of childhood epilepsy in Finland. Seizure (London, England). 2024;117:20–7.
  4 Vaajala M, Mattila VM, Kuitunen I. Fear of childbirth prolongs interpregnancy interval: A nationwide register-based quantile logistic regression analysis. European Journal of Obstetrics & Gynecology and Reproductive Biology: X. 2024;21:100281.
  5 Ax M, Palola V, Ponkilainen V, et al. Duration of sick leave after operated and non-operated distal radial fracture: a Finnish cohort study of 19,995 patients. The Journal of hand surgery, European volume. 2024;49:316–21.
  6 Valtanen K, Seikkula J, Kurtti M, et al. Ten-year patterns of psychiatric medications dispensed to adolescent in Finland: Open dialogue-informed practice in Western Lapland as compared to practice in other Finnish regions. Personalized Medicine in Psychiatry. 2024;43–44:100117.
  7 Raudasoja L, Vastamäki H, Aspinen S, et al. Distal radial fractures: a nationwide register study on corrective osteotomies after malunion. J Hand Surg Eur Vol. 2024;49:329–33.
  8 Terho AM, Tiitinen A, Salo J, et al. Growth of singletons born after frozen embryo transfer until early adulthood: a Finnish register study. Human reproduction (Oxford). 2024;39:604–11.
  9 Tamlander M, Jermy B, Seppälä TT, et al. Genome-wide polygenic risk scores for colorectal cancer have implications for risk-based screening. British journal of cancer. 2024;130:651–9.
  10 Kolari TA, Vuori M, RÄttÖ H, et al. Incidence of ADHD medication use among Finnish children and adolescents in 2008–2019: a need for practice changes? Scand J Public Health. 2024;14034948231219826.
  11 Dhejne C, Lichtenstein P, Boman M, et al. Long-Term Follow-Up of Transsexual Persons Undergoing Sex Reassignment Surgery: Cohort Study in Sweden. PLoS One. 2011;6. doi: 10.1371/journal.pone.0016885
  12 Kaltiala R, Holttinen T, Tuisku K. Have the psychiatric needs of people seeking gender reassignment changed as their numbers increase? A register study in Finland. Eur Psychiatry. 2023;66:e93.
  13 Holttinen T, Pirkola S, Kaltiala R. Schizophrenia among young people first admitted to psychiatric inpatient care during early and middle adolescence. Schizophrenia research. 2023;252:103–9.
  14 Jutta Niemi, Timo Holttinen, Riittakerttu Kaltiala. Adolescents with severe depressive and anxiety – a nationwide register study of inpatient-treated adolescents 1980- 2010. Psychiatria fennica (Online). 2023;54:66–79.

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  Conflict of Interest:
  None declared.

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• Published on: 20 March 2024

  Methods and results do not support conclusions of Ruuska et al.

  • Carl Streed, Associate Professor of Medicine Boston University Chobanian and Avedisian School of Medicine, Boston Medical Center
  • Other Contributors:
    • Kellan Baker, Executive Director
    • Howard Cabral, Professor of Biostatistics
    • Emily Sisson, Director, Statistical Programming
    • Caroline Davidge-Pitts, Endocrinologist
    • Johanna Olson-Kennedy, Medical Director, The Center for Transyouth Health and Development
    • Madeline Deutsch, Professor of Clinical Family & Community Medicine; Medical Director, UCSF Gender Affirming Health Program

  We appreciate the interest in understanding the health and well-being of transgender persons and their unique care needs, particularly youth and adolescents. There are, however, several methodological missteps in the recent article by Ruuska et al. that has been published in BMJ Mental Health. The authors have fallen into a number of methodological mistakes and fallacies that make quite untenable their conclusions that gender-affirming interventions have no effect on suicide mortality.
  First, the authors have not shared sufficient data to support their conclusions that gender-affirming interventions do not reduce suicide. A properly reported analysis must show the events and characteristics of all transgender persons referred for care, as well as the sub-groups (hormonal and/or surgical interventions vs. no interventions). Similarly, with respect to the shortfalls of their analytic methodology, the authors have not demonstrated that they checked the proportional hazards assumption on which their Cox models rely. Given the rapidly changing political and social environments for transgender people in countries around the world, including Finland, the assumption that the hazards are proportional over time must be examined and explained. The authors also violate standard practice by not showing Kaplan-Meier curves for each of the outcomes of interest, in addition to providing the rates of all-cause mortality and suicide in each risk group discussed.
  Second, with onl...

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  We appreciate the interest in understanding the health and well-being of transgender persons and their unique care needs, particularly youth and adolescents. There are, however, several methodological missteps in the recent article by Ruuska et al. that has been published in BMJ Mental Health. The authors have fallen into a number of methodological mistakes and fallacies that make quite untenable their conclusions that gender-affirming interventions have no effect on suicide mortality.
  First, the authors have not shared sufficient data to support their conclusions that gender-affirming interventions do not reduce suicide. A properly reported analysis must show the events and characteristics of all transgender persons referred for care, as well as the sub-groups (hormonal and/or surgical interventions vs. no interventions). Similarly, with respect to the shortfalls of their analytic methodology, the authors have not demonstrated that they checked the proportional hazards assumption on which their Cox models rely. Given the rapidly changing political and social environments for transgender people in countries around the world, including Finland, the assumption that the hazards are proportional over time must be examined and explained. The authors also violate standard practice by not showing Kaplan-Meier curves for each of the outcomes of interest, in addition to providing the rates of all-cause mortality and suicide in each risk group discussed.
  Second, with only seven suicides among all transgender persons referred for care (medical interventions vs. none), the authors have likely presented over-fitted adjusted Cox models given the number of covariates that were included. This is particularly evident in the very wide confidence intervals for many of the hazard ratios presented. With so few events, the authors would perhaps be reasonably expected to adjust for one variable at a time.
  Third, the authors have not presented a theoretical framework for the variables they include in their models. A directed acyclic graph (DAG) would provide important grounding in how each variable is handled and accounted for in relation to the outcome of suicide. In particular, including mental health visits—which are a component of gender-affirming care—is a fatal over-adjustment in the models that purport to show no relationship between receipt of gender-affirming care and death by suicide.
  Lastly, adjusted hazard ratios for suicide mortality were 3.2 (95% CI: 1.0 to 10.2; p=0.05) among referred persons who had not received medical and surgical interventions and 0.8 (95% CI: 0.2 to 4.0; p=0.8) among referred persons who did receive interventions, each of these compared to cisgender controls, but not each other. The clinically meaningful sizes of the hazard ratios themselves demonstrate substantial likelihood that receipt of gender-affirming care is associated with a decrease in the risk of suicide mortality. Meanwhile, the enormous confidence intervals demonstrate a lack of precision within the models, which suggest insufficient statistical power notwithstanding the large overall sample sizes examined. The authors here succumb to the fallacy that a lack of statistical difference in a testing context equates with a lack of any difference at all.
  Given the thankfully small number of suicides within the sample from Finland (7 out of 2083 identified transgender persons), it may be that a future study should pool multiple samples across comparable settings (e.g., Sweden, Norway, Netherlands, Denmark, etc.) and perform a meta-analysis. This would be understandably difficult as treatment models have not been uniform across time and geography, but this could provide sufficient power to truly explore differences in rates of suicide among transgender persons who receive medical and surgical interventions versus transgender persons who do not receive such interventions.
  The authors should exercise appropriate restraint based on available data and the methods available to analyze them.

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  Conflict of Interest:
  None declared.

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