Random forests for survival data: which methods work best and under what conditions?

Few systematic comparisons of methods for constructing survival trees and forests exist in the literature. Importantly, when the goal is to predict a survival time or estimate a survival function, the optimal choice of method is unclear. We use an extensive simulation study to systematically investigate various factors that influence survival forest performance - forest construction method, censoring, sample size, distribution of the response, structure of the linear predictor, and presence of correlated or noisy covariates. In particular, we study 11 methods that have recently been proposed in the literature and identify 6 top performers. We find that all the factors that we investigate have significant impact on the methods' relative accuracy of point predictions of survival times and survival function estimates. We use our results to make recommendations for which methods to use in a given context and offer explanations for the observed differences in relative performance.

Comparing prostatic artery embolization to surgical and minimally invasive procedures for the treatment of benign prostatic hyperplasia: a systematic review and meta-analysis.

BACKGROUND: To summarize current evidence to report a comparative systematic review and meta-analysis of prostatic artery embolization (PAE) with transurethral resection of the prostate (TURP) and open simple prostatectomy (OSP) for the treatment of benign prostatic hyperplasia (BPH). METHODS: A systematic literature search was performed to identify studies published from inception until August 2021. The search terms used were (prostate embolization OR prostatic embolization) AND (prostatic hyperplasia OR prostatic obstruction) as well as the abbreviations of PAE and BPH. Risk of bias was assessed using the Cochrane Risk of Bias tool for randomized controlled trials (RCTs) and the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) tool for observational studies. Random-effects meta-analysis was performed using Revman 5.4. RESULTS: Seven studies were included with 810 patients: five RCTs and one observational study compared PAE with TURP, and one observational study compared PAE with OSP. The included studies had considerable risk of bias concerns. TURP and OSP were associated with more statistically significant improvements in urodynamic measures and BPH symptoms compared to PAE. However, PAE seems to significantly improve erectile dysfunction compared to OSP and improve other outcome measures compared to TURP, although not significantly. PAE appeared to reduce adverse events and report more minor complications compared with TURP and OSP, but it is unclear whether PAE is more effective in the long-term. CONCLUSION: PAE is an emerging treatment option for patients with symptomatic BPH who cannot undergo surgery or have undergone failed medical therapy. Overall, PAE groups reported fewer adverse events. Future ongoing and longer-term studies are needed to provide better insight into the benefit of PAE compared to other treatment options.

Phosphatidylinositol Monophosphates Regulate the Membrane Localization of HSPA1A, a Stress-Inducible 70-kDa Heat Shock Protein.

HSPA1A is a molecular chaperone that regulates the survival of stressed and cancer cells. In addition to its cytosolic pro-survival functions, HSPA1A also localizes and embeds in the plasma membrane (PM) of stressed and tumor cells. Membrane-associated HSPA1A exerts immunomodulatory functions and renders tumors resistant to standard therapies. Therefore, understanding and manipulating HSPA1A's surface presentation is a promising therapeutic. However, HSPA1A's pathway to the cell surface remains enigmatic because this protein lacks known membrane localization signals. Considering that HSPA1A binds to lipids, like phosphatidylserine (PS) and monophosphorylated phosphoinositides (PIPs), we hypothesized that this interaction regulates HSPA1A's PM localization and anchorage. To test this hypothesis, we subjected human cell lines to heat shock, depleted specific lipid targets, and quantified HSPA1A's PM localization using confocal microscopy and cell surface biotinylation. These experiments revealed that co-transfection of HSPA1A with lipid-biosensors masking PI(4)P and PI(3)P significantly reduced HSPA1A's heat-induced surface presentation. Next, we manipulated the cellular lipid content using ionomycin, phenyl arsine oxide (PAO), GSK-A1, and wortmannin. These experiments revealed that HSPA1A's PM localization was unaffected by ionomycin but was significantly reduced by PAO, GSK-A1, and wortmannin, corroborating the findings obtained by the co-transfection experiments. We verified these results by selectively depleting PI(4)P and PI(4,5)P2 using a rapamycin-induced phosphatase system. Our findings strongly support the notion that HSPA1A's surface presentation is a multifaceted lipid-driven phenomenon controlled by the binding of the chaperone to specific endosomal and PM lipids.

Postpartum amenorrhea duration by sex of the newborn in two natural fertility populations.

OBJECTIVES: Postpartum amenorrhea (PA) affects the length of interbirth intervals and thus is intimately related to human life history strategies. PA duration appears to be influenced by maternal energetic status. In humans, as in other mammals, sons are costlier than daughters. Thus, we hypothesize that, in energetically constrained environments, a newborn's sex should be associated with PA duration. METHODS: We analyzed data from two natural fertility populations in which mothers have differing energy budgets: Qom women (n = 121) from a periurban village in Argentina, who have a comparatively calorically dense diet and are sedentary (prepregnancy mean BMI = 24.8 ± 4.5 kg/m2 in 1997), and agropastoral Kaqchikel Maya women (n = 88), who have a comparatively calorically restricted diet and high physical activity levels (mean BMI = 21.8 ± 3.7 kg/m2 ). We predict that (a) mothers of sons exhibit longer PA duration than mothers of daughters and (b) this association between offspring sex and PA duration is stronger in the Maya, who have smaller energy budgets. RESULTS: Maya mothers with sons exhibited estimated mean and median PA durations that were 1.34 times the estimated mean and median PA duration of mothers with daughters (p = 0.02). Among the Qom, mean, and median PA duration did not differ significantly in relation to offspring sex (p = 0.94). CONCLUSIONS: Maya mothers with sons exhibited longer PA duration than those with daughters. This phenomenon was not observed in the well-nourished Qom, possibly due to "buffering" effects from larger energy budgets. Offspring sex may influence birth spacing and maternal life history strategies in energetically constrained environments.

Optimizing pharmacokinetics/pharmacodynamics of ß-lactam/ß-lactamase inhibitor combinations against high inocula of ESBL-producing bacteria.

OBJECTIVES: Reduced in vitro ß-lactam activity against a dense bacterial population is well recognized. It is commonly attributed to the presence of ß-lactamase(s) and it is unknown whether the inoculum effect could be diminished by a ß-lactamase inhibitor. We evaluated different ß-lactam/ß-lactamase inhibitor combinations in suppressing a high inoculum of ESBL-producing bacteria. METHODS: Three clinical isolates expressing representative ESBLs (CTX-M-15 and SHV-12) were examined. The impact of escalating ß-lactamase inhibitor (tazobactam or avibactam) concentrations on ß-lactam (piperacillin or ceftazidime) MIC reduction was characterized by an inhibitory sigmoid Emax model. The effect of various dosing regimens of ß-lactam/ß-lactamase inhibitor combinations was predicted using %T>MICi and selected exposures were experimentally validated in a hollow-fibre infection model over 120 h. The threshold exposure to suppress bacterial regrowth was identified using recursive partitioning. RESULTS: A concentration-dependent reduction in ß-lactam MIC was observed (r2 ≥0.93). Regrowth could be suppressed in all six experiments using %T>MICi ≥73.6%, but only one out of six experiments below the threshold (P = 0.015). The exposures to suppress regrowth might be attained using the clinical dose of avibactam, but a much higher dose than the standard dose would be needed for tazobactam. CONCLUSIONS: A dense population of ESBL-producing bacteria could be suppressed by an optimized dosing regimen of selected ß-lactam/ß-lactamase inhibitor combinations. The reversibility of enzyme inhibition could play an important role in diminishing the inoculum effect. In vivo investigations to validate these findings are warranted.

Initial Canadian Experience of Prostate Artery Embolization for Symptomatic Benign Prostatic Hyperplasia: Midterm Outcomes.

INTRODUCTION: This study aimed to assess the midterm outcomes and safety of prostate artery embolization (PAE) for the treatment of benign prostatic hyperplasia (BPH). METHODS: A single-center, retrospective review of PAE performed for BPH was performed. Validated International Prostate Symptom Score (IPSS), quality of life (QoL) index, and International Index for Erectile Function (IIEF-5) questionnaires were completed at baseline and at least 12 months post-procedure. Prostate imaging was performed preprocedure as well as 3 months and 12 months post-procedure to assess prostate volume (PV). Uroflowmetry was also performed at baseline and 12 months post-procedure to assess urine flow rate (Qmax) and post-void residual (PVR) volume. Adverse events were graded according to Society of Interventional Radiology (SIR) guidelines. RESULTS: Eighty male patients underwent the PAE procedure (mean age 69 years). Prostate volume decreased significantly from a mean volume 156 to 107 mL after 12 months post-procedure, commensurate with a mean reduction of 27.5% (P < .05). Significant improvements were seen in IPSS (21.8 vs 10.5) and QoL (4.5 vs 2.0) from baseline to 12 months post-procedure (P < .05). There was no significant change in IIEF-5 score. There was a significant reduction in PVR (202 vs 105 mL) and improvement in Qmax (5.9 vs 10.0 mL/s) between baseline and 12 months post-procedure (P < .05). No major complications occurred; 4 minor complications occurred (SIR grade A or B). CONCLUSION: Prostate artery embolization achieved a clinically and statistically significant prostate volume reduction, symptom and QoL improvement, and enhanced uroflowmetry parameters in patients with BPH.

Breastfeeding Duration and the Social Learning of Infant Feeding Knowledge in Two Maya Communities.

Variation in the durations of exclusive breastfeeding (exBF) and any breastfeeding (anyBF) is associated with socioecological factors. This plasticity in breastfeeding behavior appears adaptive, but the mechanisms involved are unclear. With this concept in mind, we investigated whether durations of exBF and anyBF in a rural Maya population covary with markers of a form of socioecological change-market integration-and whether individual factors (individual learning, physiological plasticity) and/or learning from others in the community (social learning, norm adherence) mediate these changes. Using data from 419 mother-child pairs from two Guatemalan Maya villages, we fit a bivariate linear mixed model. The model compared exBF and anyBF among children from households of varying degrees of market integration whose mothers follow what we inferred to be local infant-feeding norms. It controlled for other factors expected to affect breastfeeding durations. We found evidence that exBF is associated with whether mothers follow their population's infant feeding norms, but no evidence that exBF is associated with the household's level of market integration. Conversely, anyBF is significantly associated with the household's market integration, but not with the villages' inferred norms. Because deviations from exBF norms are likely to result in infant mortality and reduced fitness, we hypothesize that the incentive to conform is relatively strong. Relatively greater individual plasticity in anyBF allows mother-child pairs to tailor it to socioecological conditions. Deviations from anyBF norms may be tolerated because they may provide later-life health/fitness payoffs, while posing few risks to infant survival.

Sex ratio and maternal age in a natural fertility, subsistence population: Daughters, sons, daughters.

OBJECTIVE: To evaluate putative links between birth sex ratios (BSR = male:female births) and maternal age in a traditional, agricultural, natural fertility population. Metabolic energy, social support, and the costs and benefits associated with producing sons versus daughters can affect BSR. These variables fluctuate with maternal age. Most studies evaluating links between maternal age and BSR have been based on industrialized populations, which differ importantly from traditional indigenous communities in terms of the aforementioned socio-ecological variables. MATERIALS AND METHODS: We analyze data from 108 mothers and their 603 children living in an agricultural, pronatalist, Kakchiquel Mayan community. RESULTS: A logistic regression model, including linear and quadratic maternal age terms and women-specific random effects, shows a nonmonotonic (p = .028) relationship between log BSR and maternal age. For maternal age ≤ 22, the upper bound of the 95% confidence interval (CI) for BSR is <1, suggesting a bias toward girls. The probability of birthing a son increased early during the average mother's reproductive career, peaked at age 31.3 (approximately 95% CI = 27.1, 35.5), and decreased as she approached her perimenopausal period (p = .014). DISCUSSION: No changes in mating system, population sex ratio, mortality patterns, natural disasters, social risk, or toxic exposures were observed and thus are unlikely to explain our results. At this point, age-related changes in metabolic energy, social support, and costs and benefits associated with offspring sex cannot be excluded as possible explanations. BSR can affect growth, morbidity, and mortality. Thus, our results are relevant to numerous fields, including anthropology, ecology, demography, and public health.

Emotional Responses to Suicidal Patients: Factor Structure, Construct, and Predictive Validity of the Therapist Response Questionnaire-Suicide Form.

BACKGROUND: Mental health professionals have a pivotal role in suicide prevention. However, they also often have intense emotional responses, or countertransference, during encounters with suicidal patients. Previous studies of the Therapist Response Questionnaire-Suicide Form (TRQ-SF), a brief novel measure aimed at probing a distinct set of suicide-related emotional responses to patients found it to be predictive of near-term suicidal behavior among high suicide-risk inpatients. The purpose of this study was to validate the TRQ-SF in a general outpatient clinic setting. METHODS: Adult psychiatric outpatients (N = 346) and their treating mental health professionals (N = 48) completed self-report assessments following their first clinic meeting. Clinician measures included the TRQ-SF, general emotional states and traits, therapeutic alliance, and assessment of patient suicide risk. Patient suicidal outcomes and symptom severity were assessed at intake and one-month follow-up. Following confirmatory factor analysis of the TRQ-SF, factor scores were examined for relationships with clinician and patient measures and suicidal outcomes. RESULTS: Factor analysis of the TRQ-SF confirmed three dimensions: (1) affiliation, (2) distress, and (3) hope. The three factors also loaded onto a single general factor of negative emotional response toward the patient that demonstrated good internal reliability. The TRQ-SF scores were associated with measures of clinician state anger and anxiety and therapeutic alliance, independently of clinician personality traits after controlling for the state- and patient-specific measures. The total score and three subscales were associated in both concurrent and predictive ways with patient suicidal outcomes, depression severity, and clinicians' judgment of patient suicide risk, but not with global symptom severity, thus indicating specifically suicide-related responses. CONCLUSION: The TRQ-SF is a brief and reliable measure with a 3-factor structure. It demonstrates construct validity for assessing distinct suicide-related countertransference to psychiatric outpatients. Mental health professionals' emotional responses to their patients are concurrently indicative and prospectively predictive of suicidal thoughts and behaviors. Thus, the TRQ-SF is a useful tool for the study of countertransference in the treatment of suicidal patients and may help clinicians make diagnostic and therapeutic use of their own responses to improve assessment and intervention for individual suicidal patients.

A comparison of the efficacy of weight-shift vs. joystick control of a robotic mobility device by infants ages 5 to 10 months.

The onset of crawling in infants contributes to cognitive, perceptual, social, and emotional development. Conversely, infants with motor impairment that delays or prevents autonomous mobility often have associated developmental delays. Evidence suggests that providing mobility may have positive developmental outcomes, however powered wheelchairs may not be recommended for very young children, due to safety concerns and the child's level of cognitive maturity. The WeeBot is a mobility device controlled by infant weight shifting while seated; infants as young as 5 months have learned to use it. This study compares the efficacy of using the WeeBot vs. using the traditional manual joystick to control a robotic mobility device. Participants were 20 typically developing infants between 5 and 10 months who had not yet achieved independent mobility. A quasi-experimental two-group design was used: The first 10 participants recruited used the WeeBot (weight-shift); the next 10 used the joystick. Results showed that infants learned to use weight-shift control more easily and more skilfully than did infants using the joystick. The ability of infants to use the WeeBot suggests that an intuitive alternative control might allow very early powered mobility for children with disabilities, which might have implications for various aspects of their development.

Practical considerations when analyzing discrete survival times using the grouped relative risk model.

The grouped relative risk model (GRRM) is a popular semi-parametric model for analyzing discrete survival time data. The maximum likelihood estimators (MLEs) of the regression coefficients in this model are often asymptotically efficient relative to those based on a more restrictive, parametric model. However, in settings with a small number of sampling units, the usual properties of the MLEs are not assured. In this paper, we discuss computational issues that can arise when fitting a GRRM to small samples, and describe conditions under which the MLEs can be ill-behaved. We find that, overall, estimators based on a penalized score function behave substantially better than the MLEs in this setting and, in particular, can be far more efficient. We also provide methods of assessing the fit of a GRRM to small samples.

The ex-pat effect: presence of recent Western immigrants is associated with changes in age at first birth and birth rate in a Maya population from rural Guatemala.

BACKGROUND: Economic transitions expose indigenous populations to a variety of ecological and cultural challenges, especially regarding diet and stress. These kinds of challenges are predicted by evolutionary ecological theory to have fitness consequences (differential reproduction) and, indeed, are often associated with changes in fertility dynamics. It is currently unclear whether international immigration might impact the nature of such an economic transition or its consequences for fertility. AIM: To examine measures of fertility, diet and stress in two economically transitioning Maya villages in Guatemala that have been differentially exposed to immigration by Westerners. SUBJECTS AND METHODS: This study compared Maya women's ages at first birth and birth rates between villages and investigated whether these fertility indicators changed through time. It also explored whether the villages differed in relation to diet and/or a proxy of stress. RESULTS: It was found that, in the village directly impacted by immigration, first births occurred earlier, but birth rate was slower. In both villages, over the sampled time window, age at first birth increased, while birth rate decreased. The villages do not differ significantly in dietary indicators, but the immigration-affected village scored higher on the stress proxy. CONCLUSION: Immigration can affect fertility in host communities. This relationship between immigration and fertility dynamics may be partly attributable to stress, but this possibility should be evaluated prospectively in future research.

Child mortality, hypothalamic-pituitary-adrenal axis activity and cellular aging in mothers.

Psychological challenges, including traumatic events, have been hypothesized to increase the age-related pace of biological aging. Here we test the hypothesis that psychological challenges can affect the pace of telomere attrition, a marker of cellular aging, using data from an ongoing longitudinal-cohort study of Kaqchikel Mayan women living in a population with a high frequency of child mortality, a traumatic life event. Specifically, we evaluate the associations between child mortality, maternal telomere length and the mothers' hypothalamic-pituitary-adrenal axis (HPAA), or stress axis, activity. Child mortality data were collected in 2000 and 2013. HPAA activity was assessed by quantifying cortisol levels in first morning urinary specimens collected every other day for seven weeks in 2013. Telomere length (TL) was quantified using qPCR in 55 women from buccal specimens collected in 2013. RESULTS: Shorter TL with increasing age was only observed in women who experienced child mortality (p = 0.015). Women with higher average basal cortisol (p = 0.007) and greater within-individual variation (standard deviation) in basal cortisol (p = 0.053) presented shorter TL. Non-parametric bootstrapping to estimate mediation effects suggests that HPAA activity mediates the effect of child mortality on TL. Our results are, thus, consistent with the hypothesis that traumatic events can influence cellular aging and that HPAA activity may play a mediatory role. Future large-scale longitudinal studies are necessary to confirm our results and further explore the role of the HPAA in cellular aging, as well as to advance our understanding of the underlying mechanisms involved.

Energy-related influences on variation in breastfeeding duration among indigenous Maya women from Guatemala.

OBJECTIVES: The causes of variation in breastfeeding duration in humans are poorly understood, but life history factors related to maternal energetics drive much of the variation in lactation duration in nonhuman animals. With this in mind, we investigated whether four energy-related factors influence variation in breastfeeding duration in a non-industrial human population: (1) mortality risk during mother's development (assessed via mother's adult height), (2) reliance on nutrient-dense weaning foods, (3) access to and need for help with infant feeding and care ("allomaternal care"), and (4) maternal tradeoffs between current and future reproduction (measured via child's birth order). MATERIALS AND METHODS: The data pertain to 51 Kakchiquel-speaking Maya mothers and 283 children from a village in rural Guatemala. We developed a linear mixed model to evaluate the relationships between breastfeeding duration and the energy-related factors. RESULTS: Duration of breastfeeding was associated with two of the energy-related factors in the ways we predicted but not with the other two. Contrary to predictions, taller mothers breastfed for shorter periods and we found no evidence that weanling diet quality impacts breastfeeding duration. As predicted, women who had more help with infants breastfed for shorter periods, and later-born infants breastfed longer than earlier-born ones. DISCUSSION: The results regarding allomaternal care suggest that help reduces mothers' lactation demands. The energy saved may be redirected to increasing fecundity or investment in other children. The birth order result suggests that children born to mothers nearing reproductive senescence receive higher levels of investment, which likely impacts children's fitness.

Number of Children and Telomere Length in Women: A Prospective, Longitudinal Evaluation.

Life history theory (LHT) predicts a trade-off between reproductive effort and the pace of biological aging. Energy invested in reproduction is not available for tissue maintenance, thus having more offspring is expected to lead to accelerated senescence. Studies conducted in a variety of non-human species are consistent with this LHT prediction. Here we investigate the relationship between the number of surviving children born to a woman and telomere length (TL, a marker of cellular aging) over 13 years in a group of 75 Kaqchikel Mayan women. Contrary to LHT's prediction, women who had fewer children exhibited shorter TLs than those who had more children (p = 0.045) after controlling for TL at the onset of the 13-year study period. An "ultimate" explanation for this apparently protective effect of having more children may lay with human's cooperative-breeding strategy. In a number of socio-economic and cultural contexts, having more chilren appears to be linked to an increase in social support for mothers (e.g., allomaternal care). Higher social support, has been argued to reduce the costs of further reproduction. Lower reproductive costs may make more metabolic energy available for tissue maintenance, resulting in a slower pace of cellular aging. At a "proximate" level, mechanisms involved may include the actions of the gonadal steroid estradiol, which increases dramatically during pregnancy. Estradiol is known to protect TL from the effects of oxidative stress as well as increase telomerase activity, an enzyme that maintains TL. Future research should explore the potential role of social support as well as that of estradiol and other potential biological pathways in the trade-offs between reproductive effort and the pace of cellular aging within and among human as well as in non-human populations.

A longitudinal model for magnetic resonance imaging lesion count data in multiple sclerosis patients.

Magnetic resonance imaging (MRI) data are routinely collected at multiple time points during phase 2 clinical trials in multiple sclerosis. However, these data are typically summarized into a single response for each patient before analysis. Models based on these summary statistics do not allow the exploration of the trade-off between numbers of patients and numbers of scans per patient or the development of optimal schedules for MRI scanning. To address these limitations, in this paper, we develop a longitudinal model to describe one MRI outcome: the number of lesions observed on an individual MRI scan. We motivate our choice of a mixed hidden Markov model based both on novel graphical diagnostic methods applied to five real data sets and on conceptual considerations. Using this model, we compare the performance of a number of different tests of treatment effect. These include standard parametric and nonparametric tests, as well as tests based on the new model. We conduct an extensive simulation study using data generated from the longitudinal model to investigate the parameters that affect test performance and to assess size and power. We determine that the parameters of the hidden Markov chain do not substantially affect the performance of the tests. Furthermore, we describe conditions under which likelihood ratio tests based on the longitudinal model appreciably outperform the standard tests based on summary statistics. These results establish that the new model is a valuable practical tool for designing and analyzing multiple sclerosis clinical trials.

Is cortisol excretion independent of menstrual cycle day? A longitudinal evaluation of first morning urinary specimens.

BACKGROUND: Cortisol is frequently used as a marker of physiologic stress levels. Using cortisol for that purpose, however, requires a thorough understanding of its normal longitudinal variability. The current understanding of longitudinal variability of basal cortisol secretion in women is very limited. It is often assumed, for example, that basal cortisol profiles do not vary across the menstrual cycle. This is a critical assumption: if cortisol were to follow a time dependent pattern during the menstrual cycle, then ignoring this cyclic variation could lead to erroneous imputation of physiologic stress. Yet, the assumption that basal cortisol levels are stable across the menstrual cycle rests on partial and contradictory evidence. Here we conduct a thorough test of that assumption using data collected for up to a year from 25 women living in rural Guatemala. METHODOLOGY: We apply a linear mixed model to describe longitudinal first morning urinary cortisol profiles, accounting for differences in both mean and standard deviation of cortisol among women. To that aim we evaluate the fit of two alternative models. The first model assumes that cortisol does not vary with menstrual cycle day. The second assumes that cortisol mean varies across the menstrual cycle. Menstrual cycles are aligned on ovulation day (day 0). Follicular days are assigned negative numbers and luteal days positive numbers. When we compared Models 1 and 2 restricting our analysis to days between -14 (follicular) and day 14 (luteal) then day of the menstrual cycle did not emerge as a predictor of urinary cortisol levels (p-value>0.05). Yet, when we extended our analyses beyond that central 28-day-period then day of the menstrual cycle become a statistically significant predictor of cortisol levels. SIGNIFICANCE: The observed trend suggests that studies including cycling women should account for day dependent variation in cortisol in cycles with long follicular and luteal phases.