Heterogeneous Treatment Effects of Therapeutic-Dose Heparin in Patients Hospitalized for COVID-19.

Importance: Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making. Objective: To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. Design, Setting, and Participants: Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. Exposures: Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. Main Outcomes and Measures: Organ support-free days, assigning a value of -1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival. Results: Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support-free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support-free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI <30) vs higher BMI groups (BMI ≥30; posterior probability of difference in ORs >90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline. Conclusions and Relevance: Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs. Trial Registration: ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT04372589.

Cohort effects in age-associated cognitive trajectories.

BACKGROUND: The age-specific prevalence and incidence of dementia and cognitive impairment in the United States have either remained stable or even slightly declined during the 1980s-1990s. A suggested but untested reason for this improvement in cognitive function over time is higher educational attainment among more recent cohorts. METHODS: We used data from two large prospective population-based epidemiological dementia studies conducted in two adjacent regions during the period 1987-2012. We examined whether (i) cohort effects could be observed in age-associated trajectories of cognitive functions and (ii) the observed cohort effects could be explained by educational attainment. Trajectories of neuropsychological tests tapping three domains (psychomotor speed, executive function, and language) were compared among cohorts born between 1902 and 1911, 1912 and 1921, 1922 and 1931, and 1932 and 1943. We examined Age × Cohort interactions in mixed-effects models with/without controlling for education effects. RESULTS: Cohort effects in age-associated trajectories were observed in all three domains, with consistent differences between the earliest born cohort and the most recent cohort. Executive functions showed the strongest and persistent differences between the most recent and other three cohorts. Education did not attenuate any of these associations. CONCLUSIONS: Cohort effects were observed in all examined cognitive domains and, surprisingly, remained significant after controlling for educational effects. Factors other than education are likely responsible for the cohort effects in cognitive decline.

Prediction of accrual closure date in multi-center clinical trials with discrete-time Poisson process models.

In a phase III multi-center cancer clinical trial or a large public health study, sample size is predetermined to achieve desired power, and study participants are enrolled from tens or hundreds of participating institutions. As the accrual is closing to the target size, the coordinating data center needs to project the accrual closure date on the basis of the observed accrual pattern and notify the participating sites several weeks in advance. In the past, projections were simply based on some crude assessment, and conservative measures were incorporated in order to achieve the target accrual size. This approach often resulted in excessive accrual size and subsequently unnecessary financial burden on the study sponsors. Here we proposed a discrete-time Poisson process-based method to estimate the accrual rate at time of projection and subsequently the trial closure date. To ensure that target size would be reached with high confidence, we also proposed a conservative method for the closure date projection. The proposed method was illustrated through the analysis of the accrual data of the National Surgical Adjuvant Breast and Bowel Project trial B-38. The results showed that application of the proposed method could help to save considerable amount of expenditure in patient management without compromising the accrual goal in multi-center clinical trials.

The Effect of Race, Sex, and Insurance Status on Time-to-Listing Decisions for Liver Transplantation.

Fair allocation of organs to candidates listed for transplantation is fundamental to organ-donation policies. Processes leading to listing decisions are neither regulated nor understood. We explored whether patient characteristics affected timeliness of listing using population-based data on 144,507 adults hospitalized with liver-related disease in Pennsylvania. We linked hospitalizations to other secondary data and found 3,071 listed for transplants, 1,537 received transplants, and 57,020 died. Among candidates, 61% (n = 1,879) and 85.5% (n = 2,626) were listed within 1 and 3 years of diagnosis; 26.7% (n = 1,130) and 95% (n = 1,468) of recipients were transplanted within 1 and 3 years of listing. Using competing-risks models, we found few overall differences by sex, but both black patients and those insured by Medicare and Medicaid (combined) waited longer before being listed. Patients with combined Medicare and Medicaid insurance, as well as those with Medicaid alone, were also more likely to die without ever being listed. Once listed, the time to transplant was slightly longer for women, but it did not differ by race/ethnicity or insurance. The early time period from diagnosis to listing for liver transplantation reveals unwanted variation related to demographics that jeopardizes overall fairness of organ allocation and needs to be further explored.

Severity of interstitial cystitis symptoms and quality of life in female patients.

OBJECTIVE: Interstitial cystitis (IC) is a visceral pain syndrome with a profound impact on quality of life (QOL). The main aims of the current study are as follows: (1) to determine possible factors that may increase the severity of symptoms and decrease QOL in women diagnosed with IC; (2) to study how symptom severity affects QOL adjusting for these factors; and (3) to investigate which symptom is most likely to impair IC patients' physical and mental QOL. METHODS: Forty-one women (age, 20-71 years) with moderate/severe IC enrolled in a clinical trial of intravesical pentosan polysulfate sodium in California (USA) were included in this cross-sectional analysis. Demographic and clinical characteristics were evaluated at baseline using the O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI), pain assessment, urgency scale, voiding log for 24 h, and the Short Form-36 (SF-36). RESULTS: Being currently unmarried was associated with more severe symptoms. Being unemployed, currently unmarried, obese, never pregnant, and ever use of oral contraceptive were associated with a decrement in at least one QOL domain. Symptom severity was an independent predictor of worse QOL on three domains: bodily pain, general health, and mental health. Pain and nocturia were the only symptoms found to be associated with decline in overall physical quality of life. None of the symptoms had significant impact on the mental component summary of QOL. CONCLUSIONS: Symptom severity and being currently unmarried were found to be associated with impairment in QOL in IC patients. Managing pain and nocturia may improve the patients' overall physical QOL.

Association of lifestyle and relationship factors with sexual functioning of women during midlife.

INTRODUCTION: As women progress through menopause, they experience changes in sexual functioning that are multifactorial, likely encompassing biological, psychological, and social domains. AIM: To examine the effects that physical activity, sleep difficulties, and social support have on partnered sexual activity and sexual functioning in women at different stages of the menopausal progression. METHODS: As part of an ongoing 5-year longitudinal study, we conducted a cross-sectional analysis of sexual functioning data. MAIN OUTCOME MEASURES: Participation in partnered sexual activities, reasons for nonparticipation in such activities among sexually inactive women, and, among sexually active women, sexual functioning defined as engagement in and enjoyment of sexually intimate activities. RESULTS: Of 677 participants aged 41-68, 68% had participated in any partnered sexual activities (i.e., were sexually active) during the past 6 months. Reasons for sexual inactivity included lack of a partner (70%), lack of interest in sex (12%) or in the current partner (5%), and physical problems (4%). Sexually active participants tended to be younger, married, more educated, have more social support in general, fewer comorbid medical illnesses, a lower body mass index, and a higher prevalence of vaginal dryness. Among the sexually active participants, their scores for engagement in activities ranging from kissing to sexual intercourse were higher if they were physically active, had more social support, and lacked sleeping difficulties. Likewise, scores for sexual enjoyment were higher if they were physically active, had more social support, and lacked vaginal dryness. Engagement and enjoyment scores were not associated with marital status or other factors. CONCLUSIONS: In midlife women, having social support and being physically active are associated with enhanced sexual engagement and enjoyment.

Vaginal maturation index self-sample collection in mid-life women: acceptability and correlation with physician-collected samples.

OBJECTIVE: During menopause, the ratio of the three vaginal epithelial cell types (parabasal, intermediate, and superficial) changes. The proportion of these vaginal cell types is categorized by the vaginal maturation index (VMI). The VMI provides an objective assessment of vaginal hormone response as well as overall hormonal environment. The aim of this study was to determine the concordance of self- and physician-collected samples for VMI and evaluate participant preference for self-collection. DESIGN: Twenty women aged 42 to 67 years were enrolled. Each woman received instructions and self-collected a sample for VMI analysis from her posterior lateral vaginal walls. Next, she underwent a vaginal speculum examination for physician VMI sampling. Finally, she completed a survey regarding sampling preference, ease of self-sampling, and previous vaginal experience. Correlation between physician- and self-collected samples were calculated using Pearson's correlation coefficient and Cronbach's alpha. Participant characteristics, vaginal experiences, and sampling preferences were summarized using frequencies and measures of central tendencies. The relationships between preference for sampling method and previous vaginal experiences were examined using Fisher's exact test. RESULTS: Average age of the 20 participants was 52.2 years (range, 42-67 y). Women had a variety of previous vaginal experiences ranging from tampon use (100%) to previous vaginal self-swabbing (15%). Average self-collected VMI was 48.4 (range, 13.8-83.5) and physician-collected VMI was 49.9 (range, 20.5-83.5) with a correlation of 0.97 (P < 0. 001), alpha = 0.94. The majority of women preferred self-collection (80%) to physician collection, and there was no difference in preference based on previous vaginal experiences. Nineteen women (95%) found the self-collection to be very easy, and one found it to be somewhat easy. CONCLUSIONS: Women can reliably self-collect samples for VMI, and the majority of women in our study preferred self-collection to physician collection. Vaginal self-sampling allows this technique for measuring overall hormonal environment to be used in clinical and epidemiological research.

Pregnancy and birth history influence women's experience of menopause.

OBJECTIVE: The determinants of experiencing menopausal symptoms are complex, representing biological, psychological, and social factors. We report the impact of one such factor, fertility, on the experience of menopausal symptoms. We hypothesize that nulliparous women will have more dissatisfaction with childbearing choices and more negative attitudes toward menopause but will experience fewer menopausal symptoms. DESIGN: Women aged 40 to 65 years were recruited from a single internal medicine practice to participate in a 5-year longitudinal study of the impact of menopause on health-related quality of life. Women completed questionnaires including the RAND-36, attitudes toward menopause, menopausal symptoms, and fertility and childbearing. Based on self-reported pregnancy and birth history, we categorized women as parous (one or more live births), nulligravida (no pregnancies or births), and nulliparous (one or more pregnancies and no live births). Categorical variables were analyzed using univariable and multivariable ordered logistic and logistic regression. Continuous variables were analyzed using Student's t test and multivariable linear regression techniques. RESULTS: The 728 participants were, on average, 50.8 years old with 2.4 pregnancies and 1.7 live births. Compared with parous women, nulligravida and nulliparous women were more likely to report being very dissatisfied with childbearing choices (odds ratio [OR] [95% CI]: 3.3 [2.3-4.6] and 4.0 [2.5-6.4], respectively). Nulliparous, but not nulligravida, women expressed more negative attitudes toward menopause compared with parous women (P<0.001). Nulligravida and nulliparous women were half as likely to report hot flashes as parous women (OR [95% CI]: 0.6 [0.4-0.9] and 0.5 [0.3-0.9], respectively). Compared with parous women, nulligravida women were less likely to report vaginal dryness (OR [95% CI]: 0.5 [0.3-0.7]). CONCLUSIONS: Our study examined the impact of pregnancy and birth history on menopausal symptoms, and the findings support the hypothesis that women who experience infertility may find menopause to be a time of normalcy and experience fewer hot flashes. Both physiologic and psychosocial mechanisms deserve further study.