A computational approach to compare regression modelling strategies in prediction research.

BACKGROUND: It is often unclear which approach to fit, assess and adjust a model will yield the most accurate prediction model. We present an extension of an approach for comparing modelling strategies in linear regression to the setting of logistic regression and demonstrate its application in clinical prediction research. METHODS: A framework for comparing logistic regression modelling strategies by their likelihoods was formulated using a wrapper approach. Five different strategies for modelling, including simple shrinkage methods, were compared in four empirical data sets to illustrate the concept of a priori strategy comparison. Simulations were performed in both randomly generated data and empirical data to investigate the influence of data characteristics on strategy performance. We applied the comparison framework in a case study setting. Optimal strategies were selected based on the results of a priori comparisons in a clinical data set and the performance of models built according to each strategy was assessed using the Brier score and calibration plots. RESULTS: The performance of modelling strategies was highly dependent on the characteristics of the development data in both linear and logistic regression settings. A priori comparisons in four empirical data sets found that no strategy consistently outperformed the others. The percentage of times that a model adjustment strategy outperformed a logistic model ranged from 3.9 to 94.9 %, depending on the strategy and data set. However, in our case study setting the a priori selection of optimal methods did not result in detectable improvement in model performance when assessed in an external data set. CONCLUSION: The performance of prediction modelling strategies is a data-dependent process and can be highly variable between data sets within the same clinical domain. A priori strategy comparison can be used to determine an optimal logistic regression modelling strategy for a given data set before selecting a final modelling approach.

Propensity score balance measures in pharmacoepidemiology: a simulation study.

BACKGROUND: Conditional on the propensity score (PS), treated and untreated subjects have similar distribution of observed baseline characteristics when the PS model is appropriately specified. The performance of several PS balance measures in assessing the balance of covariates achieved by a specific PS model and selecting the optimal PS model was evaluated in simulation studies. However, these studies involved only normally distributed covariates. Comparisons in binary or mixed covariate distributions with rare outcomes, typical of pharmacoepidemiologic settings, are scarce. METHODS: Monte Carlo simulations were performed to examine the performance of different balance measures in terms of selecting an optimal PS model, thus reduction in bias. The balance of covariates between treatment groups was assessed using the absolute standardized difference, the Kolmogorov-Smirnov distance, the Lévy distance, and the overlapping coefficient. Spearman's correlation coefficient (r) between each of these balance measures and bias were calculated. RESULTS: In large sample sizes (n ≥ 1000), all balance measures were similarly correlated with bias (r ranging between 0.50 and 0.68) irrespective of the treatment effect's strength and frequency of the outcome. In smaller sample sizes with mixed binary and continuous covariate distributions, these correlations were low for all balance measures (r ranging between 0.11 and 0.43), except for the absolute standardized difference (r = 0.51). CONCLUSIONS: The absolute standardized difference, which is an easy-to-calculate balance measure, displayed consistently better performance across different simulation scenarios. Therefore, it should be the balance measure of choice for measuring and reporting the amount of balance reached, and for selecting the final PS model.

Synchrony of Bird Migration with Global Dispersal of Avian Influenza Reveals Exposed Bird Orders.

Highly pathogenic avian influenza virus (HPAIV) A H5, particularly clade 2.3.4.4, has caused worldwide outbreaks in domestic poultry, occasional spillover to humans, and increasing deaths of diverse species of wild birds since 2014. Wild bird migration is currently acknowledged as an important ecological process contributing to the global dispersal of HPAIV H5. However, this mechanism has not been quantified using bird movement data from different species, and the timing and location of exposure of different species is unclear. We sought to explore these questions through phylodynamic analyses based on empirical data of bird movement tracking and virus genome sequences of clade 2.3.4.4 and 2.3.2.1. First, we demonstrate that seasonal bird migration can explain salient features of the global dispersal of clade 2.3.4.4. Second, we detect synchrony between the seasonality of bird annual cycle phases and virus lineage movements. We reveal the differing exposed bird orders at geographical origins and destinations of HPAIV H5 clade 2.3.4.4 lineage movements, including relatively under-discussed orders. Our study provides a phylodynamic framework that links the bird movement ecology and genomic epidemiology of avian influenza; it highlights the importance of integrating bird behavior and life history in avian influenza studies.

Time-dependent propensity score and collider-stratification bias: an example of beta2-agonist use and the risk of coronary heart disease.

Stratification and conditioning on time-varying cofounders which are also intermediates can induce collider-stratification bias and adjust-away the (indirect) effect of exposure. Similar bias could be expected when one conditions on time-dependent PS. We explored collider-stratification and confounding bias due to conditioning or stratifying on time-dependent PS using a clinical example on the effect of inhaled short- and long-acting beta2-agonist use (SABA and LABA, respectively) on coronary heart disease (CHD). In an electronic general practice database we selected a cohort of patients with an indication for SABA and/or LABA use and ascertained potential confounders and SABA/LABA use per three month intervals. Hazard ratios (HR) were estimated using PS stratification as well as covariate adjustment and compared with those of Marginal Structural Models (MSMs) in both SABA and LABA use separately. In MSMs, censoring was accounted for by including inverse probability of censoring weights.The crude HR of CHD was 0.90 [95 % CI: 0.63, 1.28] and 1.55 [95 % CI: 1.06, 2.62] in SABA and LABA users respectively. When PS stratification, covariate adjustment using PS, and MSMs were used, the HRs were 1.09 [95 % CI: 0.74, 1.61], 1.07 [95 % CI: 0.72, 1.60], and 0.86 [95 % CI: 0.55, 1.34] for SABA, and 1.09 [95 % CI: 0.74, 1.62], 1.13 [95 % CI: 0.76, 1.67], 0.77 [95 % CI: 0.45, 1.33] for LABA, respectively. Results were similar for different PS methods, but higher than those of MSMs. When treatment and confounders vary during follow-up, conditioning or stratification on time-dependent PS could induce substantial collider-stratification or confounding bias; hence, other methods such as MSMs are recommended.

A heuristic method for identifying chaos from frequency content.

The sign of the largest Lyapunov exponent is the fundamental indicator of chaos in a dynamical system. However, although the extraction of Lyapunov exponents can be accomplished with (necessarily noisy) the experimental data, this is still a relatively data-intensive and sensitive endeavor. This paper presents an alternative pragmatic approach to identifying chaos using response frequency characteristics and extending the concept of the spectrogram. The method is shown to work well on both experimental and simulated time series.

Balance measures for propensity score methods: a clinical example on beta-agonist use and the risk of myocardial infarction.

PURPOSE: Propensity score (PS) methods aim to control for confounding by balancing confounders between exposed and unexposed subjects with the same PS. PS balance measures have been compared in simulated data but limited in empirical data. Our objective was to compare balance measures in clinical data and assessed the association between long-acting inhalation beta-agonist (LABA) use and myocardial infarction. METHODS: We estimated the relationship between LABA use and myocardial infarction in a cohort of adults with a diagnosis of asthma or chronic obstructive pulmonary disorder from the Utrecht General Practitioner Research Network database. More than two thousand PS models, including information on the observed confounders age, sex, diabetes, cardiovascular disease and chronic obstructive pulmonary disorder status, were applied. The balance of these confounders was assessed using the standardised difference (SD), Kolmogorov-Smirnov (KS) distance and overlapping coefficient. Correlations between these balance measures were calculated. In addition, simulation studies were performed to assess the correlation between balance measures and bias. RESULTS: LABA use was not related to myocardial infarction after conditioning on the PS (median heart rate = 1.14, 95%CI = 0.47-2.75). When using the different balance measures for selecting a PS model, similar associations were obtained. In our empirical data, SD and KS distance were highly correlated balance measures (r = 0.92). In simulations, SD, KS distance and overlapping coefficient were similarly correlated to bias (e.g. r = 0.55, r = 0.52 and r = -0.57, respectively, when conditioning on the PS). CONCLUSIONS: We recommend using the SD or the KS distance to quantify the balance of confounder distributions when applying PS methods.

Measuring balance and model selection in propensity score methods.

PURPOSE: Propensity score (PS) methods focus on balancing confounders between groups to estimate an unbiased treatment or exposure effect. However, there is lack of attention in actually measuring, reporting and using the information on balance, for instance for model selection. We propose to use a measure for balance in PS methods and describe several of such measures: the overlapping coefficient, the Kolmogorov-Smirnov distance, and the Lévy distance. METHODS: We performed simulation studies to estimate the association between these three and several mean based measures for balance and bias (i.e., discrepancy between the true and the estimated treatment effect). RESULTS: For large sample sizes (n = 2000) the average Pearson's correlation coefficients between bias and Kolmogorov-Smirnov distance (r = 0.89), the Lévy distance (r = 0.89) and the absolute standardized mean difference (r = 0.90) were similar, whereas this was lower for the overlapping coefficient (r = -0.42). When sample size decreased to 400, mean based measures of balance had stronger correlations with bias. Models including all confounding variables, their squares and interaction terms resulted in smaller bias than models that included only main terms for confounding variables. CONCLUSIONS: We conclude that measures for balance are useful for reporting the amount of balance reached in propensity score analysis and can be helpful in selecting the final PS model.

Startup of reactors for anoxic ammonium oxidation: experiences from the first full-scale anammox reactor in Rotterdam.

The first full-scale anammox reactor in the world was started in Rotterdam (NL). The reactor was scaled-up directly from laboratory-scale to full-scale and treats up to 750 kg-N/d. In the initial phase of the startup, anammox conversions could not be identified by traditional methods, but quantitative PCR proved to be a reliable indicator for growth of the anammox population, indicating an anammox doubling time of 10-12 days. The experience gained during this first startup in combination with the availability of seed sludge from this reactor, will lead to a faster startup of anammox reactors in the future. The anammox reactor type employed in Rotterdam was compared to other reactor types for the anammox process. Reactors with a high specific surface area like the granular sludge reactor employed in Rotterdam provide the highest volumetric loading rates. Mass transfer of nitrite into the biofilm is limiting the conversion of those reactor types that have a lower specific surface area. Now the first full-scale commercial anammox reactor is in operation, a consistent and descriptive nomenclature is suggested for reactors in which the anammox process is employed.

On the experimental identification of unstable static equilibria.

This paper shows how the presence of unstable equilibrium configurations of elastic continua is reflected in the behaviour of transients induced by large perturbations. A beam that is axially loaded beyond its critical state typically exhibits two buckled stable equilibrium configurations, separated by one or more unstable equilibria. If the beam is then loaded laterally (effectively like a shallow arch) it may snap-through between these states, including the case in which the loading is applied dynamically and of short duration, i.e. an impact. Such impacts, if applied at random locations and of random strength, will generate an ensemble of transient trajectories that explore the phase space. Given sufficient variety, some of these trajectories will possess initial energy that is close to (just less than or just greater than) the energy required to cause snap-through and will have a tendency to slowdown as they pass close to an unstable configuration: a saddle point in a potential energy surface, for example. Although this close-encounter is relatively straightforward in a system characterized by a single degree of freedom, it is more challenging to identify in a higher order or continuous system, especially in a (necessarily) noisy experimental system. This paper will show how the identification of unstable equilibrium configurations can be achieved using transient dynamics.

Distributions of alternation rates in various forms of bistable perception.

Studying the temporal dynamics of bistable perception can be useful for understanding neural mechanisms underlying the phenomenon. We take a closer look at those temporal dynamics, using data from four different ambiguous stimuli. We focus our analyses on two recurrent themes in bistable perception literature. First, we address the question whether percept durations follow a gamma distribution, as is commonly assumed. We conclude that this assumption is not justified by the gamma distribution's approximate resemblance to distributions of percept durations. We instead present two straightforward distributions of reciprocal percept durations (i.e., rates) that both easily surpass the classic gamma distribution in terms of resemblance to empirical data. Second, we compare the distributions arising from binocular rivalry with those from other forms of bistable perception. Parallels in temporal dynamics between those classes of stimuli are often mentioned as an indication of a similar neural basis, but have never been studied in detail. Our results demonstrate that the distributions arising from binocular rivalry and other forms of bistable perception are indeed similar up to a high level of detail.

Reporting of covariate selection and balance assessment in propensity score analysis is suboptimal: a systematic review.

OBJECTIVES: To assess the current practice of propensity score (PS) analysis in the medical literature, particularly the assessment and reporting of balance on confounders. STUDY DESIGN AND SETTING: A PubMed search identified studies using PS methods from December 2011 through May 2012. For each article included in the review, information was extracted on important aspects of the PS such as the type of PS method used, variable selection for PS model, and assessment of balance. RESULTS: Among 296 articles that were included in the review, variable selection for PS model was explicitly reported in 102 studies (34.4%). Covariate balance was checked and reported in 177 studies (59.8%). P-values were the most commonly used statistical tools to report balance (125 of 177, 70.6%). The standardized difference and graphical displays were reported in 45 (25.4%) and 11 (6.2%) articles, respectively. Matching on the PS was the most commonly used approach to control for confounding (68.9%), followed by PS adjustment (20.9%), PS stratification (13.9%), and inverse probability of treatment weighting (IPTW, 7.1%). Balance was more often checked in articles using PS matching and IPTW, 70.6% and 71.4%, respectively. CONCLUSION: The execution and reporting of covariate selection and assessment of balance is far from optimal. Recommendations on reporting of PS analysis are provided to allow better appraisal of the validity of PS-based studies.

Failure of L-tryptophan to stimulate prolactin secretion in man.

The effect of oral L-tryptophan (90 mg/kg BW) on prolactin secretion in eight normal women studied either in the early or late follicular phase of the menstrual cycle was compared to the effect of a placebo alone. Plasma prolactin levels were measured before and at frequent intervals over a period of 240 min after the administration of the amino acid or placebo. Plasma free L-tryptophan concentrations were determined prior to and 60 min after ingestion of the amino acid in two of the women. Despite a 25-fold increase in plasma free L-tryptophan levels following the administration of this amino acid, the prolactin response to L-tryptophan was not significantly different from a placebo.

Testosterone-secreting adrenal adenoma that contained crystalloids of Reinke in an adult female patient.

We describe a testosterone-secreting adrenal adenoma that contained crystalloids characteristic of Leydig cells in a 55-year-old woman with virilization, in whom results of a steroid biochemical profile were normal except for a substantially increased serum testosterone level. After right adrenalectomy, the serum testosterone level returned to normal and has remained within the normal range 2 years postoperatively. Histologic examination confirmed the diagnosis of a testosterone-secreting adrenal adenoma with crystalloids of Reinke specific for Leydig cells. The exact pathogenesis of these testosterone-secreting adrenal adenomas is still unclear. Although crystalloids of Reinke have been identified in only three cases, their absence does not exclude a Leydig cell character in the rest of the reported cases. Our case provides additional support for the hypothesis that Leydig cells are present in the adrenal gland and may have an active role in the pathogenesis of testosterone-secreting adrenal tumors; thus, such cells should be sought in every case.

Testosterone/androstenedione ratio in the evaluation of women with ovarian androgen excess.

A plasma testosterone/androstenedione (T/A) ratio was calculated in 15 women with possible ovarian neoplasms and androgen excess and whose mean plasma concentration of testosterone approached or was greater than a twofold elevation. The T/A ratio approached unity in eight of nine patients with polycystic ovarian disease, whereas all patients with hyperthecosis and two of three patients with androgen-secreting tumors had a testosterone/androstenedione ratio above 1.5. In 13 of 16 patients with androgen-secreting tumors of the ovary reported in the literature, the testosterone/androstenedione ratio was above 1.5. An elevated testosterone/androstenedione ratio should raise the suspicion of either an ovarian androgen-secreting tumor or hyperthecosis.

Effect of an oral contraceptive on adrenal and ovarian androgenic steroids.

Seven women with hirsutism (five with polycystic ovarian disease, two with eumenorrheic hirsutism) were studied before and during the fourth and sixth cycles of oral contraceptive treatment (norethindrone/mestranol, 1 mg/0.05 mg). Plasma testosterone, androstenedione, and dehydroepiandrosterone sulfate were measured before and during treatment. Testosterone was reduced 72%, androstenedione was reduced 68.5%, and dehydroepiandrosterone sulfate was reduced 41.25% during therapy. Plasma dehydroepiandrosterone sulfate normalized in all patients with pretreatment elevation of this steroid. Norethindrone/mestranol, 1 mg/0.05 mg is capable of suppressing both ovarian and adrenal androgens in hirsute women with modest elevation of these steroids.

Hormonal findings associated with aluteal cycles.

Menstrual bleeding with no detectable luteal function was observed cyclicly in 3 infertile patients. Anovulation was suspected and documented by basal body temperature charts and repeated endometrial biopsies prior to expected menses. A sporadic anovulatory cycle in a normally ovulating volunteer was studied and the hormonal parameters included for comparison. To elucidate the significance and the possible cause of this defect, five aluteal cycles were evaluated with serum follicle stimulating hormone (FSH), luteinizing hormone (LH), total estrogen, progestin, and prolactin determinations. No similar patterns of FSH, LH, or estrogen values were observed. No abnormality of prolactin levels was noted. The lack of progestin rise and proliferative endometrial biopsies during the second half of these cycles were the only consistent findings. When clomiphene citrate therapy was instituted, a luteal phase was promptly established.

Clomiphene citrate: pharmacologic treatment of hypofertile male.

Thirty-two males were treated with clomiphene citrate for a minimum of six months, a maximum of twelve months, or until pregnancy occurred. Among these patients, thirteen pregnancies occurred. Climiphene citrate appears a reasonable pharmaceutical method for management of idiopathic oligospermia.

The effect of hyperprolactinemia on the diurnal variation of adrenal androgens.

Morning and evening plasma cortisol, dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) were measured in ten women with hyperprolactinemia secondary to pituitary adenomas and in seven control subjects with cyclic menses and normal prolactin (PRL) levels. Plasma cortisol and DHEA-S levels were comparable in both groups. A diurnal variation for cortisol and DHEA was identified and comparable in both groups. These findings indicate that PRL may not be an important physiologic regulator of adrenal androgen secretion.

Episodic luteinizing hormone release in hyperprolactinemic women.

Episodic luteinizing hormone (LH) secretion was studied in 16 hyperprolactinemic women (microprolactinoma, 12; idiopathic, 4) with amenorrhea of 1.4 to 7 years' duration. Blood samples obtained through an indwelling venous catheter at 20-minute intervals over 5 hours were assayed for LH, follicle-stimulating hormone (FSH), prolactin (PRL), and estrogen (E) (selected samples). LH pulse patterns were divided arbitrarily into high-amplitude release (LH pulse greater than 10 mIU/ml) (n = 7), low-amplitude release (LH pulse less than 10 mIU/ml (n = 6), and no release (n = 3). Mean pulse frequencies in women with high-amplitude and low-amplitude release were 2.4 +/- 0.3 (mean +/- standard error) and 1.3 +/- 0.2 pulses/5 hours and differed significantly (P greater than 0.02), whereas mean percentages of secretory increment were 155% and 62%, respectively. Mean LH concentrations in the high-amplitude (18.0 +/- 0.8 mIU/ml), low-amplitude (13.2 +/- 0.6 mIU/ml), and no-pulse groups (7.5 +/- 0.2 mIU/ml) differed significantly (P greater than 0.02). Despite the different pulse patterns, mean serum FSH, PRL, and total E concentrations were similar. The lack of episodic LH release and/or low infrequent LH release could account for the absence of cyclic hypothalamic pituitary ovarian function, although other mechanism(s) may be operative in women with augmented LH secretory pulses.