Prevalence of self-inflicted injuries among transgender and gender diverse adolescents and young adults compared to their peers: an examination of interaction with mental health morbidity.

PURPOSE: Compare occurrence of self-inflicted injuries among transgender and gender diverse (TGD) youth to that of their cisgender peers while accounting for mental health diagnoses. METHODS: Review of electronic health records from three integrated health care systems identified 1087 transfeminine and 1431 transmasculine adolescents and young adults. Poisson regression was used to calculate prevalence ratios comparing the proportion of TGD participants with at least one self-inflicted injury (a surrogate for suicide attempt) before index date (first evidence of TGD status) to the corresponding proportions in presumed cisgender male and female referents matched on age, race/ethnicity, and health plan. Interactions between gender identities and mental health diagnoses were assessed on multiplicative and additive scales. RESULTS: TGD adolescents and young adults were more likely to have a self-inflicted injury, various mental health diagnoses, and multiple mental health diagnoses than their cisgender peers. The prevalence of self-inflicted injuries among TGD adolescents and young adults was high even in the absence of mental health diagnoses. Results were consistent with positive additive interaction and negative multiplicative interaction. CONCLUSIONS: Universal suicide prevention efforts for all youth, including those with no mental health diagnoses, and more intensive suicide prevention efforts for TGD adolescents and young adults and those with at least one mental health diagnosis are warranted.

Cohort profile: pathways to care among people with disorders of sex development (DSD).

PURPOSE: The 'DSD Pathways' study was initiated to assess health status and patterns of care among people enrolled in large integrated healthcare systems and diagnosed with conditions comprising the broad category of disorders (differences) of sex development (DSD). The objectives of this communication are to describe methods of cohort ascertainment for two specific DSD conditions-classic congenital adrenal hyperplasia with 46,XX karyotype (46,XX CAH) and complete androgen insensitivity syndrome (CAIS). PARTICIPANTS: Using electronic health records we developed an algorithm that combined diagnostic codes, clinical notes, laboratory data and pharmacy records to assign each cohort candidate a 'strength-of-evidence' score supporting the diagnosis of interest. A sample of cohort candidates underwent a review of the full medical record to determine the score cutoffs for final cohort validation. FINDINGS TO DATE: Among 5404 classic 46,XX CAH cohort candidates the strength-of-evidence scores ranged between 0 and 10. Based on sample validation, the eligibility cut-off for full review was set at the strength-of-evidence score of ≥7 among children under the age of 8 years and ≥8 among older cohort candidates. The final validation of all cohort candidates who met the cut-off criteria identified 115 persons with classic 46,XX CAH. The strength-of-evidence scores among 648 CAIS cohort candidates ranged from 2 to 10. There were no confirmed CAIS cases among cohort candidates with scores <6. The in-depth medical record review for candidates with scores ≥6 identified 61 confirmed cases of CAIS. FUTURE PLANS: As the first cohort of this type, the DSD Pathways study is well-positioned to fill existing knowledge gaps related to management and outcomes in this heterogeneous population. Analyses will examine diagnostic and referral patterns, adherence to care recommendations and physical and mental health morbidities examined through comparisons of DSD and reference populations and analyses of health status across DSD categories.

Changes in Size and Demographic Composition of Transgender and Gender Non-Binary Population Receiving Care at Integrated Health Systems.

OBJECTIVE: To examine temporal changes in the number and demographic composition of transgender/gender non-binary (TGNB) population using data from integrated health care systems. METHODS: Electronic health records from Kaiser Permanente health plans in Georgia and Northern and Southern California were used to identify TGNB individuals, who sought care from January 2006 to December 2014, and the data were analyzed by year, site, age, and sex assigned at birth. RESULTS: In 2006, the number of TGNB people (and corresponding 95% CI) per 100 000 population were 3.5 (1.9, 6.3) in Georgia, 5.5 (4.8, 6.4) in Southern California, and 17 (16, 19) in Northern California. In 2014, these frequencies increased to 38 (32, 45), 44 (42, 46), and 75 (72, 78) per 100 000 population, respectively. When analyzed by age, the most rapid increase was observed among persons 18 to 25 years old, and this increase accelerated after 2010. The ratio of transmasculine to transfeminine persons also changed from 1:1.7 in 2006 to 1:1 in 2014 overall and from 1:1 in 2006 to 1.8:1 in 2014 among persons <18 years of age. CONCLUSION: This analysis confirms previous observations that the proportion of TGNB people is growing, especially among young adults. The composition of the TGNB population is also changing from predominantly transfeminine to roughly 1:1 overall and to predominantly transmasculine in children and adolescents.

Suicide Attempts Among a Cohort of Transgender and Gender Diverse People.

INTRODUCTION: Transgender and gender diverse people often face discrimination and may experience disproportionate emotional distress that leads to suicide attempts. Therefore, it is essential to estimate the frequency and potential determinants of suicide attempts among transgender and gender diverse individuals. METHODS: Longitudinal data on 6,327 transgender and gender diverse individuals enrolled in 3 integrated healthcare systems were analyzed to assess suicide attempt rates. Incidence was compared between transmasculine and transfeminine people by age and race/ethnicity and according to mental health status at baseline. Cox proportional hazards models examined rates and predictors of suicide attempts during follow-up. Data were collected in 2016, and analyses were conducted in 2019. RESULTS: During follow-up, 4.8% of transmasculine and 3.0% of transfeminine patients had at least 1 suicide attempt. Suicide attempt rates were more than 7 times higher among patients aged <18 years than among those aged >45 years, more than 3 times higher among patients with previous history of suicide ideation or suicide attempts than among those with no such history, and 2-5 times higher among those with 1-2 mental health diagnoses and more than 2 mental health diagnoses at baseline than among those with none. CONCLUSIONS: Among transgender and gender diverse individuals, younger people, people with previous suicidal ideation or attempts, and people with multiple mental health diagnoses are at a higher risk for suicide attempts. Future research should examine the impact of gender-affirming healthcare use on the risk of suicide attempts and identify targets for suicide prevention interventions among transgender and gender diverse people in clinical settings.

Longitudinal Changes in Hematologic Parameters Among Transgender People Receiving Hormone Therapy.

CONTEXT: The effect of gender-affirming hormone therapy (HT) on erythropoiesis is an area of priority in transgender health research. OBJECTIVE: To compare changes in hematologic parameters and rates of erythrocytosis and anemia among transgender people to those of cisgender controls. DESIGN: Longitudinal observational study. PARTICIPANTS AND SETTING: We compared 559 transfeminine (TF) and 424 transmasculine (TM) people enrolled in 3 integrated health care systems to matched cisgender referents. INTERVENTIONS AND OUTCOME: Hormone therapy receipt was ascertained from filled prescriptions. Hemoglobin (Hb) and hematocrit (Hct) levels were examined from the first blood test to HT initiation, and from the start of HT to the most recent blood test. Rates of erythrocytosis and anemia in transgender participants and referents were compared by calculating adjusted hazard ratios and 95% confidence intervals (CI). RESULTS: In the TF group, there was a downward trend for both Hb and Hct. The corresponding changes in the TM cohort were in the opposite direction. TM study participants experienced a 7-fold higher rate (95% CI: 4.1-13.4) of erythrocytosis relative to matched cisgender males, and an 83-fold higher rate (95% CI: 36.1-191.2) compared to cisgender females. The corresponding rates for anemia were elevated in TF subjects but primarily relative to cisgender males (hazard ratio 5.9; 95% CI: 4.6-7.5). CONCLUSIONS: Our results support previous recommendations that hematological parameters of transgender people receiving HT should be interpreted based on their affirmed gender, rather than their sex documented at birth. The clinical significance of erythrocytosis following testosterone therapy, as well as anemia following feminizing HT, requires further investigation.

Cross-sex Hormones and Acute Cardiovascular Events in Transgender Persons: A Cohort Study.

Background: Venous thromboembolism (VTE), ischemic stroke, and myocardial infarction in transgender persons may be related to hormone use. Objective: To examine the incidence of these events in a cohort of transgender persons. Design: Electronic medical record-based cohort study of transgender members of integrated health care systems who had an index date (first evidence of transgender status) from 2006 through 2014. Ten male and 10 female cisgender enrollees were matched to each transgender participant by year of birth, race/ethnicity, study site, and index date enrollment. Setting: Kaiser Permanente in Georgia and northern and southern California. Patients: 2842 transfeminine and 2118 transmasculine members with a mean follow-up of 4.0 and 3.6 years, respectively, matched to 48 686 cisgender men and 48 775 cisgender women. Measurements: VTE, ischemic stroke, and myocardial infarction events ascertained from diagnostic codes through the end of 2016 in transgender and reference cohorts. Results: Transfeminine participants had a higher incidence of VTE, with 2- and 8-year risk differences of 4.1 (95% CI, 1.6 to 6.7) and 16.7 (CI, 6.4 to 27.5) per 1000 persons relative to cisgender men and 3.4 (CI, 1.1 to 5.6) and 13.7 (CI, 4.1 to 22.7) relative to cisgender women. The overall analyses for ischemic stroke and myocardial infarction demonstrated similar incidence across groups. More pronounced differences for VTE and ischemic stroke were observed among transfeminine participants who initiated hormone therapy during follow-up. The evidence was insufficient to allow conclusions regarding risk among transmasculine participants. Limitation: Inability to determine which transgender members received hormones elsewhere. Conclusion: The patterns of increases in VTE and ischemic stroke rates among transfeminine persons are not consistent with those observed in cisgender women. These results may indicate the need for long-term vigilance in identifying vascular side effects of cross-sex estrogen. Primary Funding Source: Patient-Centered Outcomes Research Institute and Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Mental Health of Transgender and Gender Nonconforming Youth Compared With Their Peers.

BACKGROUND: Understanding the magnitude of mental health problems, particularly life-threatening ones, experienced by transgender and/or gender nonconforming (TGNC) youth can lead to improved management of these conditions. METHODS: Electronic medical records were used to identify a cohort of 588 transfeminine and 745 transmasculine children (3-9 years old) and adolescents (10-17 years old) enrolled in integrated health care systems in California and Georgia. Ten male and 10 female referent cisgender enrollees were matched to each TGNC individual on year of birth, race and/or ethnicity, study site, and membership year of the index date (first evidence of gender nonconforming status). Prevalence ratios were calculated by dividing the proportion of TGNC individuals with a specific mental health diagnosis or diagnostic category by the corresponding proportion in each reference group by transfeminine and/or transmasculine status, age group, and time period before the index date. RESULTS: Common diagnoses for children and adolescents were attention deficit disorders (transfeminine 15%; transmasculine 16%) and depressive disorders (transfeminine 49%; transmasculine 62%), respectively. For all diagnostic categories, prevalence was severalfold higher among TGNC youth than in matched reference groups. Prevalence ratios (95% confidence intervals [CIs]) for history of self-inflicted injury in adolescents 6 months before the index date ranged from 18 (95% CI 4.4-82) to 144 (95% CI 36-1248). The corresponding range for suicidal ideation was 25 (95% CI 14-45) to 54 (95% CI 18-218). CONCLUSIONS: TGNC youth may present with mental health conditions requiring immediate evaluation and implementation of clinical, social, and educational gender identity support measures.

Manganese superoxide dismutase and breast cancer recurrence: a Danish clinical registry-based case-control study, and a meta-analysis.

BACKGROUND: Manganese superoxide dismutase (MnSOD) inhibits oxidative damage and cancer therapy effectiveness. A polymorphism in its encoding gene (SOD2: Val16Ala rs4880) may confer poorer breast cancer survival, but data are inconsistent. We examined the association of SOD2 genotype and breast cancer recurrence (BCR) among patients treated with cyclophosphamide-based chemotherapy (Cyclo). We compared our findings with published studies using meta-analyses. METHODS: We conducted a population-based case-control study of BCR among women in Jutland, Denmark. Subjects were diagnosed with non-metastatic breast cancer from 1990-2001, received adjuvant Cyclo, and were registered in the Danish Breast Cancer Cooperative Group. We identified 118 patients with BCR and 213 matched breast cancer controls. We genotyped SOD2 and used conditional logistic regression to compute the odds ratio (OR) and associated 95% confidence intervals (95% CI) of BCR. We used random-effects meta-analytic models to evaluate the association of SOD2 polymorphisms and BCR. RESULTS: The frequency of the SOD2-Ala allele was 70% in cases versus 71% in controls; 40% versus 44% were heterozygotes, and 30% versus 25% were homozygotes, respectively. Heterozygote and homozygote carriers of the Ala allele had no increased rate of BCR (OR = 1.1, 95%CI = 0.65, 2.0, and OR = 0.87, 95%CI = 0.47, 1.6, respectively). Five studies informed the meta-analytic models; summary estimates associating BCR for homozygote, or any inheritance of the variant Ala allele were 1.18 (95%CI = 0.74, 1.88), and 1.18, (95%CI = 0.91, 1.54), respectively. CONCLUSION: Our findings do not suggest that MnSOD enzymatic activity, as measured by SOD2 genotype, affects rates of BCR among patients treated with Cyclo.

Delayed radiotherapy for breast cancer patients in integrated delivery systems.

OBJECTIVE: To identify factors associated with delayed radiotherapy (RT) in older women with early-stage breast cancer. METHODS: We studied 541 women age >or=65 years diagnosed with early-stage breast cancer in 1990-1994 at 5 integrated healthcare delivery systems and treated with breast-conserving surgery and RT, but not chemotherapy. We examined whether demographic, tumor, or treatment characteristics were associated with RT delays of >8 weeks postsurgery using chi(2) tests and multivariable logistic regression. RESULTS: Seventy-six women (14%) had delayed RT, with a median delay of 14 weeks. Even though they had insurance and access to care, nonwhite and Hispanic women were much more likely than white women to have delayed RT (odds ratio = 3.3; 95% confidence interval = 1.7, 10) in multivariable analyses that controlled for demographic and clinical variables. CONCLUSIONS: Timely RT should be facilitated through physician and patient education, navigation, and notification programs to improve quality of care. Queues for RT appointments should be evaluated on an ongoing basis to ensure adequate access. Future research should examine modifiable barriers to RT timeliness and whether delays impact long-term outcomes.

Mortality impact of less-than-standard therapy in older breast cancer patients.

BACKGROUND: The purpose of this study was to compare the rates of all-cause and breast cancer-specific mortality after breast-conserving surgery (BCS) only, BCS plus radiation therapy (RT), mastectomy, and the receipt of adjuvant tamoxifen in a large population-based cohort of older women with early-stage disease. STUDY DESIGN: This cohort study was conducted within six US integrated health-care delivery systems. Automated administrative databases, medical records, and tumor registries were used to identify women aged 65 years or older who received BCS or mastectomy to treat stage I or II breast cancer diagnosed from January 1, 1990, through December 31, 1994. We compared cause-specific 10-year mortality rates across treatment categories by fitting Cox proportional hazards models adjusted for demographics and tumor characteristics. RESULTS: We identified 1,837 women having operations for stage I or II breast cancer. Compared with women receiving mastectomy, those receiving BCS without RT were twice as likely to die of breast cancer (adjusted hazards ratio [HR]=2.19, 95% confidence interval [CI], 1.51 to 3.18). Breast cancer mortality rates were similar between women receiving BCS plus RT and women receiving mastectomy (adjusted HR=1.08, 95% CI, 0.79 to 1.48). In the subset of 886 chemotherapy-naive women treated with tamoxifen, those treated with tamoxifen for less than 1 year had a substantially higher breast cancer mortality rate than those exposed 5 years or more (adjusted HR=6.26, 95% CI, 3.10 to 12.64). CONCLUSIONS: Our findings indicate that older women receiving BCS alone have higher rates of breast cancer death than those receiving BCS + RT or mastectomy and that the survival benefit from tamoxifen increases with increasing duration of treatment.

Under utilization of surveillance mammography among older breast cancer survivors.

BACKGROUND: Annual surveillance mammography is recommended for follow-up of women with a history of breast cancer. We examined surveillance mammography among breast cancer survivors who were enrolled in integrated healthcare systems. METHODS: Women in this study were 65 or older when diagnosed with early stage invasive breast cancer (N = 1,762). We assessed mammography use during 4 years of follow-up, using generalized estimating equations to account for repeated measurements. RESULTS: Eighty-two percent had mammograms during the first year after treatment; the percentage declined to 68.5% in the fourth year of follow-up. Controlling for age and comorbidity, women who were at higher risk of recurrence by being diagnosed at stage II or receiving breast-conserving surgery (BCS) without radiation therapy were less likely to have yearly mammograms (compared to stage I, odds ratio [OR] for stage IIA 0.72, confidence interval [CI] 0.59, 0.87, OR for stage IIB 0.75, CI 0.57, 1.0; compared to BCS with radiation, OR 0.58, CI 0.43, 0.77). Women with visits to a breast cancer surgeon or oncologist were more likely to receive mammograms (OR for breast cancer surgeon 6.0, CI 4.9, 7.4, OR for oncologist 7.4, CI 6.1, 9.0). CONCLUSIONS: Breast cancer survivors who are at greater risk of recurrence are less likely to receive surveillance mammograms. Women without a visit to an oncologist or breast cancer surgeon during a year have particularly low rates of mammography. Improvements to surveillance care for breast cancer survivors may require active participation by primary care physicians and improvements in cancer survivorship programs by healthcare systems.

Mammography surveillance and mortality in older breast cancer survivors.

PURPOSE: There are more than 2,000,000 breast cancer survivors in the United States today. While surveillance for asymptomatic recurrence and second primary is included in consensus recommendations, the effectiveness of this surveillance has not been well characterized. Our purpose is to estimate the effectiveness of surveillance mammography in a cohort of breast cancer survivors with complete ascertainment of surveillance mammograms and negligible losses to follow-up. PATIENTS AND METHODS: We enrolled 1,846 stage I and II breast cancer patients who were at least 65 years old at six integrated health care delivery systems. We used medical record review and existing databases to ascertain patient, tumor, and therapy characteristics, as well as receipt of surveillance mammograms. We linked personal identifiers to the National Death Index to ascertain date and cause of death. We matched four controls to each breast cancer decedent to estimate the association between receipt of surveillance mammogram and breast cancer mortality. RESULTS: One hundred seventy-eight women died of breast cancer during 5 years of follow-up. Each additional surveillance mammogram was associated with a 0.69-fold decrease in the odds of breast cancer mortality (95% CI, 0.52 to 0.92). The protective association was strongest among women with stage I disease, those who received mastectomy, and those in the oldest age group. CONCLUSION: Given existing recommendations for post-therapy surveillance, trials to compare surveillance with no surveillance are unlikely. This large observational study provides support for the recommendations, suggesting that receipt of surveillance mammograms reduces the rate of breast cancer mortality in older patients diagnosed with early-stage disease.

Breast cancer treatment of older women in integrated health care settings.

PURPOSE: A substantial literature describes age-dependent variations in breast cancer treatment, showing that older women are less likely to receive standard treatment than younger women. We sought to identify patient and tumor characteristics associated with the nonreceipt of standard primary tumor and systemic adjuvant therapies. PATIENTS AND METHODS: We studied 1,859 women age 65 years or older with stage I and II breast cancer diagnosed between 1990 and 1994 who were cared for in six geographically dispersed community-based health care systems. We collected demographic, tumor, treatment, and comorbidity data from electronic data sources, including cancer registry, administrative, and clinical databases, and from subjects' medical records. RESULTS: Women 75 years of age or older and women with higher comorbidity indices were more likely to receive nonstandard primary tumor therapy, to not receive axillary lymph node dissection, and to not receive radiation therapy after breast-conserving surgery (BCS). Asian women were less likely to receive BCS, and African American women were less likely to be prescribed tamoxifen. Although nonreceipt of most therapies was associated with a lower baseline risk of recurrence, an important minority of high-risk women (16% to 30%) did not receive guideline therapies. CONCLUSION: Age is an independent risk factor for nonreceipt of effective cancer therapies, even when comorbidity and risk of recurrence are taken into account. Information regarding treatment effectiveness in this age group and tools that allow physicians and patients to estimate the benefits versus the risks of therapies, taking into account age and comorbidity burden, are critically needed.

A sensitivity analysis of a randomized controlled trial of zinc in treatment of falciparum malaria in children.

BACKGROUND: The randomized trial has long been recognized as a means to assess the efficacy of new interventions, because the investigator can reduce or eliminate many sources of error. As such, clinical trials often do not include quantitative assessments of the extent that systematic error could affect their results. We examined the impact of different sources of bias on a randomized controlled trial of the efficacy of zinc as an adjuvant to malaria therapy in reducing time to total parasite clearance. METHODS: Using data from a previously published study, we identified two sources of bias and used the sensitivity analysis technique developed by Lash and Fink to assess the impact of each source of bias on the outcome. RESULTS: After correcting for each source of bias and reincorporating random error into our results, the point estimate of effect comparing those who received placebo to those who received zinc changed slightly (SMR changed from 0.92 to 0.90) but the 95% interval increased 22% (changing from 0.73-1.16 in the conventional analysis to 0.65-1.26 in the sensitivity analysis). CONCLUSIONS: The findings of this sensitivity analysis serve as a reminder that the frequentist confidence interval underestimates the total error, even in a randomized controlled trial. Authors of randomized controlled trial investigations ought to conduct a complete assessment of the impact of potential sources of bias in their studies. CONSORT guidelines for reporting trial results should be updated to encourage authors to assess the impact of non-random errors on their studies.