 Research article
 Open Access
 Published:
LASSO type penalized spline regression for binary data
BMC Medical Research Methodology volumeÂ 21, ArticleÂ number:Â 83 (2021)
Abstract
Background
Generalized linear mixed models (GLMMs), typically used for analyzing correlated data, can also be used for smoothing by considering the knot coefficients from a regression spline as random effects. The resulting models are called semiparametric mixed models (SPMMs). Allowing the random knot coefficients to follow a normal distribution with mean zero and a constant variance is equivalent to using a penalized spline with a ridge regression type penalty. We introduce the least absolute shrinkage and selection operator (LASSO) type penalty in the SPMM setting by considering the coefficients at the knots to follow a Laplace double exponential distribution with mean zero.
Methods
We adopt a Bayesian approach and use the Markov Chain Monte Carlo (MCMC) algorithm for model fitting. Through simulations, we compare the performance of curve fitting in a SPMM using a LASSO type penalty to that of using ridge penalty for binary data. We apply the proposed method to obtain smooth curves from data on the relationship between the amount of pack years of smoking and the risk of developing chronic obstructive pulmonary disease (COPD).
Results
The LASSO penalty performs as well as ridge penalty for simple shapes of association and outperforms the ridge penalty when the shape of association is complex or linear.
Conclusion
We demonstrated that LASSO penalty captured complex doseresponse association better than the Ridge penalty in a SPMM.
Background
The association between the level of a continuous variable and the mean response at that level may take any functional form. To reduce bias resulting from misspecifying the functional form and also from the loss of efficiency in testing induced by categorizing continuous variables, the use of nonparametric (flexible) regression models is often recommended to model the effect of variables recorded on a continuous scale [1, 2].
Nonparametric regression techniques, by their nature, do not require any parametric representation to be specified a priori, and instead determine the shape of the association directly from the data. While several competing approaches are available for such modeling (see, e.g., [3â€“14]), we focus on penalized splines (Psplines) which is a powerful technique to fit a smooth curve to the data in a scatterplot. In Psplines, a greater degree of smoothness is achieved by specifying a large number of knots and imposing restrictions on the knot coefficients to prevent overfitting [15]. An important issue, however, is to select a suitable value for the smoothing parameter, which is not a trivial task.
Penalized splines can be viewed as a particular case of generalized linear mixed models (GLMMs). To achieve a smooth function, the GLMM can be used to shrink the regression coefficients of knot points from a regression spline towards zero, by including them as random effects and constraining them to follow a normal distribution with mean zero and constant variance. The resulting models are called semiparametric mixed models (SPMMs) [13]. The main advantage of this approach is that the smoothing parameter, which controls the tradeoff between bias and variance, may be directly estimated from the data [16]. Moreover, we can take full advantage of existing methods and software for GLMMs.
Restricting the changes in the slope at the knots to follow a normal distribution with mean zero and constant variance is equivalent to using a penalized spline by imposing a ridge penalty (L_{2} penalization), that is, restricting the sum of squares of the spline coefficients at knot points to be less than a judiciously selected constant [16]. However, imposing L_{1} penalization (i.e., restricting the sum of absolute values of the knot coefficients) is also possible. By constraining the coefficients at knots to follow independent and identical Laplace (i.e., double exponential) distributions with means zero will give rise to a LASSO type penalty in a SPMM setting.
A LASSO type penalty has previously been used in a penalized spline setting (see, for example, [17â€“22]) but primarily for variable selection. The literature on curve fitting by LASSO penalty is sparse; to our knowledge, it has never been used or investigated in a SPMM setting for nonGaussian outcomes. Because of the nature of the LASSO constraint, it shrinks some coefficients and sets others to zero, and hence may be hypothesized to produce a smoother fit.
In this paper we introduce the LASSO type penalty under the SPMM framework of curve fitting and investigate if the performance of curve fitting by SPMM can be improved using the LASSO penalty rather than using a typical ridge penalty. For estimation we adopt the Bayesian approach and use Markov Chain Monte Carlo (MCMC) algorithm. Recent development in Bayesian computational software has facilitated smoothing under full Bayesian framework via mixed model representation of penalized splines (see, [13, 15, 16, 23â€“28]).
We consider binary responses and smoothing of a single continuous covariate, and systematically compare the performance of curve fitting using two penalties (LASSO and ridge), by simulation. We apply the proposed method to estimate the effect of (amount of cigarette) smoking on the risk of developing COPD.
Methods
Penalized spline models for binary data
We introduce the idea of penalized spline regression with the following simple logistic model:
where Y_{i} is a binary response variable, x_{i} a continuous covariate measured on subject i and m(Â·) is a smooth function. To estimate m(x) we use lowrank thinplate (LRTP) splines [29] with K knots \(t_{1}, \dots, t_{K}\) as given by
where \(\beta _{0}, \beta _{1}, u_{1}, \dots, u_{K}\) are regression coefficients. For \(k = 1, \dots, K\), the basis functions are:
in which w_{i}(k) is the (i, k)th element of the penalty matrix \(\Omega _{K}^{1/2}\), where the (i, k)th entry of Î©_{K} is t_{i}âˆ’t_{k}^{3} for 1â‰¤i,kâ‰¤K. The LRTP has the advantage of using a relatively small number of knots to obtain a smoother fit. It also has good mixing properties in the MCMC analysis (see, e.g., [15]). Other basis functions that are often used include truncated polynomial splines [16], natural cubic splines[30], Bsplines [12], and thin plate regression splines [29].
Denoting \( {Y} = (Y_{1}, \dots, Y_{n})^{T}, {X} = \left [1, x_{i}\right ]_{1\le i \le n}, {Z} = \left [b_{1}(x_{i}), \dots, b_{K}(x_{i})\right ]_{1\le i \le n}, {\beta }= (\beta _{0}, \beta _{1})^{T}\) and \({u}= (u_{1}, \dots, u_{K})^{T}\), Eqs. 1 and (2) can be written more compactly in matrix notation as
Model (3) is purely parametric and easily estimated as an ordinary logistic regression model. This approach is known as regression spline smoothing. Here, the u_{k} represent changes in slope from one segment to the next. So, unconstrained estimation of the u_{k} would lead to a â€œoverly fluctuating" fit due to the large number of truncated polynomials. An optimum fit could be achieved by imposing a penalty on the spline coefficients. Specifically, one could choose a large number of knots (typically 5 to 20, as suggested by Ruppert [31]) and prevent overfitting by putting a constraint on the spline coefficients. Constraints that can be imposed on u_{k} are: (i) \(\sum u_{k}^{2} \le c\), (ii) \(\sum \lvert u_{k} \rvert \le c\), and (iii) max u_{k}â‰¤c. Here, câ‰¥0 is the tuning parameter. Restrictions (i) and (ii) are known as â€˜ridgeâ€™ and â€˜LASSOâ€™ type penalties, respectively [31, 32]. Each of these constraints will lead to a smoother fit for an appropriate choice of c. However, the ridge penalty is used most frequently as it is much easier to implement.
Denoting \({\theta } = \left [\mathbb {\beta }, u \right ]^{T} \) and W=[X,Z]=[w_{i}]_{1â‰¤iâ‰¤n}, we can write (for \(i = 1, \dots, n\))
The log likelihood function for Î¸ is given by
The LASSO constraint \(\sum \lvert u_{k} \rvert \le c\) is equivalent to the addition of a penalty term \(\lambda \sum \limits _{k=1}^{K}\lvert {u_{k}} \rvert \) to the joint loglikelihood of Î¸ so that the constrained loglikelihood function is
where Î»â‰¥0 is the smoothing parameter which controls the tradeoff between the goodness of fit and smoothness of the estimated curves. The Î» can be either selected by the user or chosen via numerous methods including crossvalidation, generalized crossvalidation and a variant of Steinâ€™s unbiased estimate of risk [32].
Similarly, imposing the typical ridge penalty \(\sum u_{k}^{2} \le c\) yields a restricted maximization equation as
Bayesian approach to penalized spline
Tibshirani [32] noted that u_{k} in (6) is proportional to the negative logdensity of a Laplace (doubleexponential) distribution. Therefore, the LASSO penalized spline estimate can be obtained as the Bayes posterior mode under independent doubleexponential, DE(0,Ï„) priors for the u_{k} with mean 0 and variance 2Ï„^{2},
with Î»=1/Ï„. Again, \({u^{2}_{k}}\) in (7) is proportional to the negative logdensity of a normal distribution. As a result, the Bayesian analogue of the ridge regression type penalization involves using normal priors for the u_{k}â€™s,
with Î»=1/2Ïƒ^{2}. A fully Bayesian hierarchical modeling involves specifying a hyper prior distribution for Î». Typically, a noninformative prior that guarantees a unimodal full posterior is recommended (see, e.g., [33]).
In general, a Bayesian approach for penalized spline involves a prior distribution on u_{k} specifying that each u_{k} is likely to be near 0 which is encoded by the mean of 0 for the prior distribution. By shrinking u_{k} towards zero, the changes in gradient between consecutive line (or curve) segments are reduced to achieve a greater degree of smoothness.
The use of a doubleexponential prior on the knot coefficients puts more mass near 0 and in the tails as compared to that of using a Gaussian prior. This reflects the greater tendency of the LASSO penalty to produce estimates that are either 0 or large. As a result, the LASSO penalty shrinks those knot coefficients with minimal values towards 0 (generally faster than the ridge penalty).
Penalized splines as mixed models
Using any of the priors (8) and (9), the logistic regression spline model (3) is in fact a logistic mixed effects model
for response vector Y, known design matrices X and Z, fixed effects parameter vector Î², random effects vector u, and a diagonal variance covariance matrix Î›_{Î³}=Î³^{2}I_{K} in which Î³^{2} is the variance of u_{k}. Thus, the nonlinear association between an outcome and covariates can be modeled using penalized splines within the framework of a mixed effects model, which allows us using current methodology and software for GLMMs. The main advantage of this approach is that the smoothing parameter can be estimated directly from the data in a maximum likelihood or Bayesian framework. Moreover, using a single model, we can analyze correlated and overdispersed data by adding random effects to the additive predictor, while estimating nonlinear covariate effects by penalized splines. Note that this penalized splines approach can be easily extended to any outcome distribution that belongs to an exponential family.
The likelihood estimation of GLMMs involves a high dimensional integral over the unobserved random effects. In general, the likelihood does not have a closedform as the integral is intractable, and has to be approximated or evaluated numerically. Two popular approximation techniques are penalized quasilikelihood (PQL) [34] and (full) Laplace approximation [35]. However, both methods yield biased estimates in curve fitting under SPMM framework, especially for binary data [36, 37]. More refined approximation methods using adaptive Gaussian quadrature are not feasible as the GLMMs representation of the penalized splines involve a large number of random effects [38]. An attractive alternative to likelihoodbased approximations is to pursue a Bayesian approach that enjoys exact inference under Bayesian machinery. Bayesian methods have good frequentist properties when the model is correct but are known to be computationally intensive. Moreover, they require specification of prior distributions which is often not a trivial task, especially for variance components (see, e.g., [39]).
Nevertheless, Crainiceanu et al. [15] strongly recommend Bayesian methods for penalized splines by noting at least two potential problems of using approximated likelihoodbased estimation. First, the approximation can have a considerable effect on parameter estimation, especially on the variance components. Secondly, the confidence intervals are obtained by replacing the estimated parameters instead of the true parameters and ignoring the inherent additional variability. This results in narrower (than they should be) confidence intervals. We therefore adopt a Bayesian approach to fit the SPMMs in this paper.
Bayesian estimation
Bayesian analysis considers all unknown parameters as random variables and characterizes any previous knowledge about parameters by assigning prior distributions to them preceding the data collection. The marginal posterior distribution of parameters given the data are then used as the basis of inference. The posterior densities are, however, analytically unavailable in many cases, especially for complex models. In such cases, the Markov Chain Monte Carlo (MCMC) procedure is used to make inferences by drawing samples from all posterior distributions of interest and calculating the posterior means, medians, quantilebased confidence bands and predictive distributions.
Prior Specification for Fixed Effects For each element of the fixed effects vector Î², we consider \(\beta _{j} \thicksim N(0, \sigma ^{2}_{j})\), where \(\sigma ^{2}_{j}\) is a large constant to regard the prior as noninformative. We take \(\sigma ^{2}_{j} = 10^{6}\) to ensure a proper joint posterior distribution of the parameters under appropriate priors for the variance components.
Priors for Variance Components The variance component estimates in Bayesian mixed models are sensitive to the prior specification [39]. For the SPMMs, it is therefore crucial to choose appropriate priors for variance components as curve estimation greatly depends on the variance components. For the variance components Î³âˆˆ{Ï„,Ïƒ} in (10), perhaps the most popular choice is a highly dispersed inversegamma (IG) prior. However, for estimating SPMMs, the IG prior underestimates the variance parameters and oversmooth the nonparametric functions [36, 37]. Gelman [39] suggested using a wide ranged uniform prior density on variance parameters Î³, for example,
In case Î³ is very close to zero, Gelman [39] suggested using a special case of the halft distribution with df = 1, known as the halfCauchy distribution:
with a large value for the scale parameter s, for example, s=25. Later on, in the simulation scenarios, we try out several of these different priors and investigate the influence of those.
Markov Chain Monte Carlo Inference Assuming independence of prior distributions, the joint posterior distribution of Î¸=(Î²,u) and Î³ is given by
Our main interests are to find the posterior marginal distributions p(Î¸y) and p(Î³y). The joint posterior (13) does not have a closed form in most cases, and even if it does, we have to perform multiple integration to obtain the marginal distribution for each coefficient of the parameter vectors Î¸ and Î³. These integrals are analytically intractable for most problems. Moreover, the large dimensionality of the integrals hinders the use of numerical integration. A standard solution is to apply MCMC to draw samples from (13) to approximate (the properties of) the marginal posterior distributions of each parameter. A thorough coverage of the MCMC algorithm is provided by Gilks, Richardson and Spiegelhalter [40].
While several software platforms (such as WinBUGS, OpenBUGS, JAGS, INLA, STAN) are now available for GLMM fitting via MCMC sampling, we use JAGS (Just Another Gibbs Sampler) [41] to fit Bayesian models. JAGS is a mature and declarative language for Bayesian model fitting with reasonable computation time and a nice link to R. We call JAGS from inside of R using the R package R2jags [42] and export results to R. Other alternatives to R2jags include rjags [43] and runjags [44].
Frequentist methods for curve fitting
We also consider two popular frequentist approaches: (i) Generalized Additive Model (GAM) of Hastie and Tibshirani [10] as implemented in R package gam [45] (ii) GAM of Wood [11] as implemented in R package mgcv [46].
The gam package uses a backfitting algorithm for model fitting in which the nonparametric smoothing terms are represented by local regression or smoothing splines. The amount of smoothing is controlled by the userspecified degrees of freedom (df). In gam, few df results in a less bumpy but possibly more biased estimate, while many df results in a more flexible curve, with increased risk of overfitting [10]. The default df in gam is the trace of the implicit smoother matrix minus 1.
In mgcv package, the model is estimated by maximizing a quadratically penalized likelihood. The smooth functions are represented by penalized regression splines using optimal basis functions. The basis dimension (or number of knots) are userspecified and are chosen to be neither too small to avoid oversmoothing nor too large to avoid computational cost. The default basis dimension in mgcv is arbitrary. The smoothing parameter is selected by Generalized Cross Validation (GCV) [47] or UnBiased Risk Estimator (UBRE)[14] or Akaike Information Criteria (AIC) [48] or Laplace approximation to Restricted Maximum Likelihood (REML) [14] or by regression splines with fixed degrees of freedom, although the REML appeared to be most effective choice [46]. The confidence interval is obtained by employing a Bayesian approach to variance estimation.
Evaluation of performance
To systematically compare the performance of smoothing in a SPMM using LASSO type penalty versus ridge regression penalty (SPMMLASSO vs. SPMMRIDGE), we carried out a series of simulations with data simulated from and analyzed using logistic regression models with smooth terms.
Methods
Data generation
Data were generated from a binary distribution considering three different shapes of association between the probability of a positive outcome and covariate. We considered the sample size of n=500. For each configuration, 1,000 datasets were simulated.
Using one independent continuous covariate x, binary responses (Ys) were generated according to the model
where the covariate x was simulated from a U(0,1) and the smooth function m(Â·) took one of the three test functions shown in Table 1. The functions were scaled so that the success probability was in the range [0.02,0.98]. The overall prevalence of a positive (Y=1) outcome was kept at 0.5. We considered one simple curve (concave), one complex curve (double hump), and one linear function as the functional form for the association between the covariate and the probability of a positive outcome. A linear function was chosen to verify how well the smooth function recaptured it as a check similar to whether the nominal level of significance (probability of type I error) holds in the hypothesis testing.
Analysis of simulated datasets
Each simulated dataset was analysed by fitting a logistic (mixed effects) model of the form (14) in which the smooth term was represented by a penalized spline using LASSO or ridge penalty. We adopted lowrank thinplate splines with several knot points. For penalized splines, the number of parameters to be penalized are represented by the number of knots, and the magnitude and number of parameters to be penalized have important consequences. Thus, we considered three different number of knot points: 7, 20 and 35. These choices of knots were following Harrel [30], Rupert [31] and Wand [49]. Harrell [30] argued that using 47 knots usually results in a reasonable fit if the knots partition the data into evenly sized groups, whereas Ruppert [31] recommended taking a large number of knots (typically 5 to 20) to ensure the desired flexibility. Wand [49] suggested choosing the number of knots (K) as
and specifying the knot positions as
Representing the penalized spline as mixed model component, we estimated the model parameters using a Bayesian approach where noninformative priors were used for all parameters. Specifically, N(0,10^{6}) distributions were used for all fixed effects, while a Uniform (0, 100) prior specification was considered for each variance component. We also fitted models using HalfCauchy prior with scale parameter set to 25 (i.e., HalfCauchy (25)) for each variance component and check the sensitivity of the results to this choice. The Bayesian estimates were medians from 55,000 iterations of the MCMC algorithm after discarding the first 5,000 iterations as burnin. We ran a single chain and thinned it by keeping every 50th iteration. All simulations and analyses were carried out in R software and the MCMC was performed using JAGS (see, Supplementary Material for R code).
For each of the simulated dataset, we also adopted two frequentist GAMs as implemented in R packages: (i) gam, and (ii) mgcv. In gam, we considered smoothing splines for estimating smooth functions and used four different df: 7, 20, 35 and using default. In the mgcv package, the smooth functions were represented using penalized thin plate regression splines. The smoothing parameter was estimated during model fitting by REML. We specified four different number of basis dimensions: 7, 20, 35 and using default.
Measures of performance
The overall performance of the estimator \(\hat {m}(x)\) was evaluated using the following criteria: (i) mean average squared distance/error (MASE) from the true curves; (ii) pointwise 95% mean average coverage probabilities (MACPs); and (iii) pointwise 95% mean average confidence interval lengths (MACLs).
The pointwise MASE was defined as the mean over the 1,000 replicated datasets of the average squared error,
The 95% pointwise MACP and MACL were obtained as the means of the 1,000 average coverage probabilities (ACP) and average credible intervals lengths (ACL), respectively. We defined
where 1(.) denotes an indicator function; \(\hat {m}_{L}\) and \(\hat {m}_{U}\) are the lower and upper limits of the pointwise CI, respectively. To asses the fit at the boundary of each simulated function, we additionally computed all these performance indicators also separately for the lower and upper 10% range of the covariate.
To compare the fits graphically, we plotted the mean fitted values of the nonparametric functions and smoothed 95% pointwise coverage probabilities of the true functions. At each observed value of x, the mean fitted value was obtained by taking the average over the 1,000 replications. The smoother for coverage probability was obtained using penalized thin plate regression splines while considering logittransformed coverage probabilities from 1,000 replications as continuous outcome.
Results of the simulation study
Simulation results when two different penalties were used in penalized splines fitting are summarized in Table 2 and, exemplarily for one shape of association (double hump shape), in Fig. 1.
The penalized spline under a mixed model framework using either LASSO or ridge penalty performed well in recapturing the true curves. The mean average squared distances (MASEs) were reasonably small and the mean average coverage probabilities (MACPs) were generally near nominal level in most cases. However, for the linear and complex (double hump) shapes of association, the LASSO penalty overall performed better than the ridge penalty in terms of all performance indicators irrespective of the number of knots considered. For simple (concave) shape of association, both penalties performed quite similarly. At the boundaries (<10% and >90% of the ranges of x values), the LASSO penalty always performed better than ridge penalty in all cases.
As we increased the number of knots (K), the overall change in curve fitting performance was not remarkable except for the complex (double hump) shape of association. In general, with larger K, the MACP and MACL were larger for both penalties in all considered cases with very few exceptions. The MASE, however, showed different patterns depending on the shape of association. More specifically, for larger K, the MASEs were smaller for linear shape of association and larger for double hump shape of association for both penalties. For the concave shape of association, the MASEs fluctuated (for both penalties) as K increased.
Figure 2 illustrates the ability of the SPMM using two different penalties to recapture the true functions for K=35. The upper panel of Fig. 2 presents the true curves m_{j}(x),j=1,2,3 and the estimated curves \(\hat {m}_{j}(x)\) based on 1,000 replications. The SPMM using either (LASSO or ridge) penalty recovered the true curves reasonably well for all the shapes. However, for the linear association, the SPMMLASSO fit was relatively close to the true line especially at the borders. For the concave shape, both penalties yielded very similar fits. For the complex (double hump) shape, the reconstructed nonparametric functions had noticeable negative biases when curvature was high. However, the SPMMLASSO worked well in estimating the high curvature and tail areas as compared to SPMMRIDGE.
The lower panel of Fig. 2 compares the empirical pointwise coverage probabilities of the 95% confidence intervals of three test functions obtained from SPMMs using two different penalties. For the linear shape of association, the coverage probabilities of the credible intervals from both penalties were slightly above the nominal value of 95%. The SPMMLASSO coverage probabilities were higher than that of SPMMRIDGE throughout the range of x values. For concave shape, the coverage probabilities from both penalties agreed slightly better with the nominal value (95%) throughout the range of x except at the boundaries. For the double hump shape, the coverage probabilities of the CIs from both penalties were higher than the nominal value (95%), except at boundaries and where biases in the estimated nonparametric functions were noticeable. At xvalues where the bias was visible, CIs from both penalties yielded low coverage probabilities, but nonetheless SPMMLASSO had better coverage than SPMMRIDGE.
Results from the frequentist methods are summarized in Supplementary Tables S2 and S3. Overall, the findings were consistent with that of the Bayesian approach. In most of the simulation scenarios, the Bayesian methods had slightly better performance in recapturing the true curves.
Sensitivity analysis
We also carried out a number of other simulations using (i) HalfCauchy(25) priors for the variance components; (ii) truncated quadratic splines ; and (iii) natural cubic splines. For HalfCauchy (25) priors, the overall results were very close to those reported above. Both the truncated quadratic splines and the natural cubic splines yielded inferior fits as compared to the lowrank thinplate splines. However, in both cases the LASSO penalty performed better than using the ridge penalty, especially for complex shapes (see Supplementary Table S1).
Application to COPD data
In this section we used the SPMM to study the association between amount of smoking and risk of chronic obstructive pulmonary disease (COPD). We also investigated the association between the risk of COPD and some occupational variables after adjusting for potential confounders using data from the initial crosssectional phase of the Canadian cohort of obstructive lung disease (CanCOLD) study [50].
Methods
Data and variables
The data on 6,592 adults aged 40 or above were obtained from the initial (baseline) crosssectional phase of the prospective longitudinal CanCOLD study. The CanCOLD study is a large, prospective, populationbased, multisite study of COPD. Healthy non smokers, smokers without COPD and subjects with COPD were recruited from nine urban cities across Canada by random telephone digit dialling to identify eligible adults who were then invited to attend a clinic visit to complete questionnaires and to perform prebronchodilator and postbronchodilator spirometry (See [51] for complete details). Data used in this study were collected between August 2005 and May 2009.
We used data from the baseline visit that contained information on subjectsâ€™ COPD status (normal, at risk, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I, GOLD stage II, GOLD stage III, GOLD stage IV), demographic characteristics, smoking history and occupation. Although there were 6,592 subjects in the study, we excluded 28 participants with the following criteria: (i) reported cigarette pack years less than zero or greater than 150; (ii) participants with implausible BMI values less than 9 or greater than 60; and (iii) reported smoking more than 60 cigarettes per day. We therefore analysed data from 6,564 individuals.
Focus on smoking history
While various factors may effectively contribute to the development of COPD, smoking is far and away the primary cause of the disease, according to the World Health Organization (http://www.healthline.com/health/copd/smoking). Thus when looking for other modifiable risk factors for the COPD, it is important to adjust for smoking in the best way possible. An essential measure of smoking intensity is â€˜pack yearsâ€™ calculated as the number of packs smoked per day multiplied by number of smoking years. As the pack years is a continuous variable, its effect on the COPD occurrence may be nonlinear rather than linear. When a nonlinear effect is evident (or apparent), adjusting for a linear effect is likely to lead to residual confounding [52].
We used the SPMM to model the effect of pack years on the risk of COPD (binary outcome, COPD: 0 = no, 1 = yes) nonparametrically. More specifically, we fit the model
where Î²_{0} is the intercept of the model, m_{1} is some smooth function of pack years and \(i = 1, \dots, 6564\).
We then evaluated the effect of occupational exposures (such as asbestos, chemical manufacturing, welding, hard rock mining, coal mining) on COPD, one by one, with and without adjusting for the effects of potential confounders: pack years, age, sex, and BMI. Note that due to the multiple response allowed for the occupational exposure, different occupational categories considered in this study were not mutually exclusive. For example, an individual working in a steel mill/factory was also reported in the occupational exposure group of welding, and chemical/plastic manufacturing. As such, we could not include the occupation as a single categorical variable in the model. For estimating the adjusted effect we fit the model
where m_{j},j=1,2,3 are smooth functions, x_{i} are fixed effect covariates that include an intercept, a binary (yes/no) occupation variable and sex, and Î² are fixed effect parameters.
Following simulation results, which suggested that the Bayesian SPMM using LASSO penalty had relatively better curve fitting performance than other frequentist and Bayesian methods, we only adopted the Bayesian SPMM imposing LASSO type penalty for curve fitting. Each of the smooth functions in (16) and (17) was estimated by using penalized lowrank thinplate regression splines with a large number of knots K=20, where knot positions were specified as in (15). Considering LASSO penalty, we imposed the centering constraint on each smoother such that the sum of the elements of each smoother m_{j}(.) is zero (see, [14] for details). Representing each smoother as a mixed model component, we estimate the model parameters using a Bayesian approach via MCMC sampling. Noninformative prior distributions were used for all fixed effects and variance components (N(0,10^{6}) and Uniform(0,100), respectively). To estimate each model, we ran 2 chains and the estimates were medians from 55,000 iterations after discarding the initial 5,000 iterations of burnin. Both chains were thinned by keeping every 50th iteration. A 95% posterior credible interval for each parameter of interests was obtained as 2.5th and 97.5th percentiles of the posterior sample. We evaluated convergence of the chains by visually examining the trace plot, density plot, sample autocorrelation function for each parameter, and also following Gelman and Rubin [53] to quantify the betweenchain and the withinchain variability of a quantity of interest.
Results of the data analysis
Table 3 presents the demographic characteristics, smoking behavior and occupational exposure types in the entire cohort, stratified by COPD status. Approximately 21% participants were diagnosed with COPD. Compared to nonCOPD participants, COPD participants were older, included more men, more smokers, and more pack years of smoking, had a higher proportion of smokers who had quit smoking, and had a slightly higher proportion of occupational exposure to hard rock, coal, asbestos, chemical, steel, welding and sawmilling.
For all models fit via MCMC simulation, we observed good mixing properties of the chains with fat hairy caterpillars like trace plots, similar density plots, and few significant autocorrelations. The GelmanRubin \(\sqrt {(\hat {R})}\) values [53] for the estimates were all less than 1.03 indicating good convergence of the chains.
The first panel of Fig. 3 shows the estimated nonparametric functions of pack years obtained from fitting model (16) using a LASSO penalty. It is clearly apparent that the association between pack years and COPD was nonlinear. The risk of COPD increased sharply until about 60 pack years and then flattened out.
Results from all models fits to evaluate the association between occupational variables and COPD are summarized in Table 4. All of the considered occupational variables including hard rock mining, coal mining, working with asbestos, chemical/plastics manufacturing, foundry/steel milling, welding, sawmilling were found to have a statistically significant impact on the risk of the prevalence of COPD when considering unadjusted models. However, none of these variables significantly affected COPD when the models were properly adjusted for the effects of potential confounders.
The estimated shape of the pack yearsCOPD association from the adjusted model (17) (where occupational variable was hard rock mining) was the same as shown in the first panel of Fig. 3. Also, the estimated nonparametric functions of age and BMI from adjusted model are shown in the second and third panels of Fig. 3, respectively. It is evident that the age of the participants was linearly associated with COPD prevalence whereas the BMICOPD association was slightly nonlinear. Low BMI was associated with an increased risk, and a lowered risk with increasing BMI plateaued off at BMI 40.
Discussion
Under the semiparametric mixed model (SPMM), we introduced the LASSO type absolute penalty to investigate if the performance of curve fitting can be improved over that using a typical ridge penalty.
We adopted a fully Bayesian approach to estimate SPMMs for binary outcomes. Via simulations, we assembled evidence suggesting that using a LASSO penalty is an eligible competitor to the typical ridge regression type penalty. We evaluated the relative performance of the penalties in three different scenarios: linear, simple (concave function) and complex (double hump) shapes of association.
Test results suggested that the LASSO penalty performed better than the ridge penalty in recapturing the linear and complex functional forms between continuous predictor and binary outcome. For simpler nonlinear association both penalties performed similarly. These results may be due to the fact that, for linear association, there are a large number of very small regression coefficients at knots to be penalized and the LASSO penalty does a better job in shrinking them towards zero. Tibshirani [32] showed that the LASSO defines a continuous shrinking operation that can produce coefficients that are exactly zero. Relatively more shrinkage of all small knot coefficients towards zero leads to a straight line fit rather than curvature. For the complex shape, there are a small to moderate number of large or moderatesized regression coefficients at knots. In such cases, the LASSO penalty puts more weight on large coefficients and, hence, may perform better to estimate the curvature areas as compared to the ridge penalty, which penalizes all regression coefficients almost uniformly. Finally, for the simple nonlinear shape (concave function) of association, there are a large number of very small or moderatesized coefficients to be shrunk and in such situations both penalties perform similarly.
Note that in a linear regression setting, LASSO is a worthy competitor to subset selection and ridge regression, outperforming other methods when there are a small to moderate number of moderatesized effects [32]. Similarly, the LASSO penalized SPMMs for curve fitting does not significantly outperform its closest contender the ridge penalty in all cases but performs better in scenarios where the curvature is high or the association is linear, although the LASSO penalty yielded better fit around boundaries in all considered cases.
Overall, we found that the Bayesian estimates of the nonparametric functions were not very sensitive to the choice of prior distributions for the variance components. Results from using uniform priors for variance components were very similar to those obtained using halfCauchy priors. Lowrank thinplate splines were found to perform better than natural cubic splines or truncated quadratic splines, confirming the results in Crainiceanu et al. [15]: a good choice of basis function has important consequences for the mixing properties of the MCMC chains in Bayesian analysis.
We also found that the Bayesian methods had marginally better performance than the popular frequentist methods for curve fitting in most cases. However, because of the differences in estimation techniques, representation of smooth functions, choice of splines and basis functions, selection of smoothing parameter, the observed differences in frequentist and Bayesian methods may be due to any number of reasons, not necessarily the type of penalty imposed.
We applied the proposed Bayesian method to identify the association between some occupational variables and chronic obstructive pulmonary disease (COPD) after investigating the shape of the smokingCOPD association using data from the Canadian cohort of obstructive lung disease (CanCOLD) study. We found that the smokingCOPD association was nonlinear. To identify potential occupational risk factors for COPD, while minimizing the risk of residual confounding, it is crucial to adjust for smoking appropriately and that seemed to be using a smooth function given that the shape is not linear. After adjusting for smoking pack years, age, sex and BMI, we found all occupational variables had statistically insignificant effects on COPD.
In this paper, we included both simulated and real datasets. However, the range of simulation scenarios investigated was not exhaustive. For simplicity, and to avoid intensive computational efforts, we smoothed only one covariate in the simulation. The extension to smooth multiple covariates in a SPMM is straightforward and we demonstrated this on an example from CanCOLDCOPD data.
Conclusion
The promising results from this study suggest that the LASSO penalty might better capture complex doseresponse association. However, the Bayesian estimation of SPMM using LASSO penalty is relatively complex and time consuming; it might take relatively threefold more time compared to ridge penalty.
Availability of data and materials
In this paper we use secondary data from the initial crosssectional phase of the Canadian cohort of obstructive lung disease (CanCOLD) study. The data are not available online and required administrative permission. We were granted permission for using this data by Dr. Jean Bourbeau.
Abbreviations
 GLMM:

Generalized linear mixed model
 SPMM:

Semiparametric mixed model
 LASSO:

Least absolute shrinkage and selection operator
 MCMC:

Markov Chain Monte Carlo
 COPD:

Chronic obstructive pulmonary disease
 LRTP:

Lowrank thinplate spline
 DE:

Doubleexponential
 PQL:

Penalized quasilikelihood
 IG:

Inversegamma
 JAGS:

Just another Gibbs sampler
 MASE:

Mean average squared error
 MACP:

Mean average coverage probability
 MACL:

Mean average confidence interval length
 BMI:

Body mass index
 CanCOLD:

Canadian cohort of obstructive lung disease
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Acknowledgments
We are thankful to Drs. Jean Bourbeau and Wan Tan for providing access to the COPD data of the CanCOLD study. We also thank two reviewers whose comments have improved this manuscript.
Funding
This research was partially supported by Dr. Benedettiâ€™s grant from the Fonds de recherche SantÃ©QuÃ©bec (FRQS). The funding body had no role in designing the study and collection, or in the analysis, or in the interpretation of the data or in writing the manuscript.
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MM, JH and AB determined the overall scope of this study. MM planned the analytical strategies, analyzed the data, interpreted the results, designed and carried out simulation study and wrote the manuscript, and AB supervised the whole work. JH offered feedback on the data analysis and manuscript and contributed interpreting the results. All authors read and approved the final manuscript.
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Additional file 1
Supplementary Material: This file contains three tables that summarize additional simulation results and R code.
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Mullah, M., Hanley, J.A. & Benedetti, A. LASSO type penalized spline regression for binary data. BMC Med Res Methodol 21, 83 (2021). https://doi.org/10.1186/s12874021012349
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DOI: https://doi.org/10.1186/s12874021012349
Keywords
 Penalized splines
 Generalized linear mixed models
 Ridge regression
 Least absolute shrinkage and selection operator (LASSO)
 Markov chain Monte Carlo