Thinking outside the curve, part II: modeling fetalinfant mortality
 Richard Charnigo^{1}Email author,
 Lorie W Chesnut^{2},
 Tony LoBianco^{3} and
 Russell S Kirby^{4}
DOI: 10.1186/147123931044
© Charnigo et al; licensee BioMed Central Ltd. 2010
Received: 27 November 2009
Accepted: 12 August 2010
Published: 12 August 2010
Abstract
Background
Greater epidemiologic understanding of the relationships among fetalinfant mortality and its prognostic factors, including birthweight, could have vast public health implications. A key step toward that understanding is a realistic and tractable framework for analyzing birthweight distributions and fetalinfant mortality. The present paper is the second of a twopart series that introduces such a framework.
Methods
We propose estimating birthweightspecific mortality within each component of a normal mixture model representing a birthweight distribution, the number of components having been determined from the data rather than fixed a priori.
Results
We address a number of methodological issues related to our proposal, including the construction of confidence intervals for mortality risk at any given birthweight within a component, for odds ratios comparing mortality within two different components from the same population, and for odds ratios comparing mortality within analogous components from two different populations. As an illustration we find that, for a population of white singleton infants, the odds of mortality at 3000 g are an estimated 4.15 times as large in component 2 of a 4component normal mixture model as in component 4 (95% confidence interval, 2.04 to 8.43). We also outline an extension of our framework through which covariates could be probabilistically related to mixture components. This extension might allow the assertion of approximate correspondences between mixture components and identifiable subpopulations.
Conclusions
The framework developed in this paper does not require infants from compromised pregnancies to share a common birthweightspecific mortality curve, much less assume the existence of an interval of birthweights over which all infants have the same curve. Hence, the present framework can reveal heterogeneity in mortality that is undetectable via a contaminated normal model or a 2component normal mixture model.
Background
A recent report shows a slight decline in the rate of infants with low birthweights (less than 2500 g) in the United States, with a rate of 8.2 percent in 2007 compared to 8.3 percent in 2006 [1]. While the rate for extremely low (ELBW; <1000 g) and very low birthweights (VLBW; 10001500 g) was unchanged at 1.5 percent, the rate for moderately low birthweights (MLBW; 15002500 g) declined from 6.8 to 6.7 percent [1]. Data on the proportions of normal (NBW; 25004000 g) and high birthweights (HBW; >4000 g) were not provided. If confirmed in the final vital records data, the decline in the low birthweight rate will be the first in many years. National Center for Health Statistics (NCHS) records indicate that low birthweight rates have been rising since 1984, when the rate was 6.7 percent [1].
Perinatal epidemiologists have long recognized birthweight as one of several factors related to fetal growth, and ultimately, infant survival and development [2–4]. However, categories such as ELBW and VLBW, while useful for descriptive purposes, are not completely satisfactory for representing the birthweight distribution of a population, much less assessing the relationship between birthweight and fetalinfant mortality. First, cutoffs such as 1500 g and 2500 g are arbitrary and introduce an artificial discreteness to a naturally continuous phenomenon: presumably fetalinfant mortality risk decreases only incrementally as one moves from, for example, 2499 g to 2501 g. Second, there may still be heterogeneity at any fixed birthweight: some infants born at, say, 2499 g may be at higher risk than other infants born at 2499 g.
where k is the number of components, x is birthweight, p _{ j }is the fraction of births in component j, μ _{ j }is the mean of the birthweights in component j, σ _{ j }is the standard deviation of the birthweights in component j, and f (x; μ _{ j }, σ _{ j }) is the probability density for a normal distribution with mean μ _{ j }and standard deviation σ _{ j }. What distinguished our proposal from the contaminated normal model of Umbach and Wilcox [5] and the 2component normal mixture model of Gage and Therriault [6] was that the number of components was not fixed a priori but rather determined from the data using the Flexible Information Criterion (FLIC) (Pilla and Charnigo, Consistent estimation and model selection in semiparametric mixtures, submitted). We also showed how to construct confidence intervals for p _{ j }, μ _{ j }, and σ _{ j }(1 <= j <= k) based on multiple samples from the same population, even if those samples overlapped.
Here we consider estimating birthweightspecific mortality curves within each component of the normal mixture model in Equation (1). We begin by generalizing Gage's parametric mixtures of logistic regressions (PMLR) technique [7] to accommodate a normal mixture model with more than two components. We proceed to show how confidence bounds can be constructed for birthweightspecific mortality curves. We then provide formulas for estimating mortality odds ratios comparing populations on the same component, such as
odds of mortality at 2500 g in component 3 (white heavy smoking population) divided by
odds of mortality at 2500 g in component 3 (white general population),
or comparing components in the same population, such as
odds of mortality at 1000 g in component 2 (white heavy smoking population) divided by
odds of mortality at 1000 g in component 1 (white heavy smoking population).
Being able to estimate the latter kind of odds ratio  in other words, being able to assert that some infants in a population are at higher risk than others, even when they are of the same birthweight  is the main advantage of modeling a birthweight distribution as we have proposed, rather than using a contaminated normal model [5] or a 2component normal mixture model [6]. Thus, our twopart series provides a modeling framework through which heterogeneity in mortality can be revealed that might otherwise remain undetected.
Results
1. Mortality risk estimation from a single sample
a. Description of the methodology
Gage developed a parametric mixtures of logistic regressions (PMLR) technique to estimate mortality risk as a function of birthweight within each of two components in a normal mixture model describing a birthweight distribution [7]. Although PMLR was formulated for a 2component model, we generalize it to k components as follows.
Gage took p _{ j }(x) to be a seconddegree polynomial, allowing the birthweightspecific mortality curves for each of his two components to be Ushaped [7]. However, since our framework permits more than two components, we are reluctant to assume that a Ushaped pattern should prevail within every component. Thus, we take p _{ j }(x) to be a fourthdegree polynomial, which accommodates up to two changes in convexity for each birthweightspecific mortality curve.
Since estimates of p _{ j }, μ _{ j }, and σ _{ j }(1 <= j <= k) are required to calculate the Flexible Information Criterion (FLIC) (Pilla and Charnigo, Consistent estimation and model selection in semiparametric mixtures, submitted) when determining the number of components, we may assume that these estimates are now available. We then employ the optimization (optim) procedure in version 2.3.1 of R (R Foundation for Statistical Computing, Vienna, Austria, 2006) to estimate r _{1}(x) through r _{ k }(x) by maximum likelihood conditional on the estimates of p _{ j }, μ _{ j }, and σ _{ j }(1 <= j <= k). Thus, PMLR represents the second half of a twostage procedure for modeling birthweight distribution and fetalinfant mortality. Our R code is available upon written request to the corresponding author. Section I of [Additional file 1] provides details on initial value specification for PMLR.
b. An illustrative example
We continue the example from Section 2a of Results from the previous paper, involving a data set of size 50,000 from the NCHS PublicUse Perinatal Mortality Data. This data set was a random sample from the population of 202,849 white singletons who were born (or experienced fetal death) from 2000 to 2002 and whose mothers smoked heavily (at least twenty cigarettes per day). Equation (5) in our previous paper shows the estimates of p _{ j }, μ _{ j }, and σ _{ j }(1 <= j <= 4) from the FLICselected 4component model. Using these estimates, we employed PMLR as described above to estimate r _{1}(x) through r _{4}(x).
Birthweightspecific mortality appears roughly Ushaped within component 3. The patterns for the other components are decreasing rather than Ushaped, although the decrease for component 2 plateaus in the HBW range. The decrease for component 4 actually becomes steeper in the HBW range, but this seems to be an artifact: the proportion of births in component 4 is small, and there are rather few deaths at large birthweights, so estimating birthweightspecific mortality within component 4 at large birthweights is difficult. The modelimplied mortality curve tracks empirical mortality very closely when the denominators for the crude rates are not too small.
c. Results from competing models for birthweight distribution
We used the same data set to estimate birthweightspecific mortality curves for the lower residual and predominant distributions in a contaminated normal model (Figure 1b) [5]. Since the estimated proportion of births in the upper residual distribution was less than 1 in 8700, we did not attempt to estimate a birthweightspecific mortality curve for the upper residual distribution.
The modelimplied mortality curve generally appears reasonable, although there is an artifact at the threshold of 1700 g, where the lower residual distribution terminates. The contaminated normal model asserts that all infants at any fixed birthweight greater than 1700 g (and less than 5300 g, if one considers the upper residual distribution) have the same mortality risk. Moreover, since the predominant distribution is virtually nonexistent in the VLBW and ELBW ranges, the contaminated normal model cannot detect heterogeneity in mortality risk at any fixed birthweight in the VLBW and ELBW ranges.
We also estimated birthweightspecific mortality curves for the primary and secondary distributions in a 2component normal mixture (Figure 1c) [6]. The modelimplied mortality curve appears reasonable except for the pronounced downturn at 5100 g, which is an artifact of the extremely small denominators above 5000 g.
The 2component normal mixture can detect heterogeneity in the NBW range and parts of the MLBW and HBW ranges. However, since the primary distribution is virtually nonexistent in the VLBW and ELBW ranges, the 2component normal mixture cannot detect heterogeneity in those ranges.
2. Mortality risk estimation from multiple samples
a. Confidence bounds
To quantify uncertainty in the estimation of birthweightspecific mortality, we proceed as follows. First, we draw N _{ rep }samples from the population of interest, where each sample consists of birthweight/mortality outcome pairs. Second, we fit a kcomponent normal mixture model to the birthweight data in each sample. Third, we apply PMLR to the birthweight and mortality outcome data in each sample, which yields estimated birthweightspecific mortality curves for that sample. Fourth, we use the N _{ rep }sets of estimated birthweightspecific mortality curves to create overall estimates of the risk functions and accompanying confidence bounds, as described below.
The rationale for using the logit transformation in Equation (4), as well as in the elements entering Equations (5) and (6) below, is described in Section II of [Additional file 1].
where ${\stackrel{\wedge}{B}}_{\theta}$ is a bias adjustment and C is a constant chosen so that the confidence interval has the desired coverage probability (typically 95%).
If Equation (6) is used, we obtain ${\stackrel{\wedge}{B}}_{\theta}$ by simulation. More specifically, we randomly generate birthweights from $\sum _{j=1}^{k}{\stackrel{\wedge}{p}}_{j}f(x;{\stackrel{\wedge}{\mu}}_{j},{\stackrel{\wedge}{\sigma}}_{j})$, where ${\stackrel{\wedge}{p}}_{1},{\stackrel{\wedge}{\mu}}_{1},{\stackrel{\wedge}{\sigma}}_{1},...,{\stackrel{\wedge}{p}}_{k},{\stackrel{\wedge}{\mu}}_{k},{\stackrel{\wedge}{\sigma}}_{k}$ are the overall estimates of their respective parameters; see Section 2c of Results from the previous paper. Then we use ${\stackrel{\wedge}{r}}_{1}(x),{\stackrel{\wedge}{r}}_{2}(x),...,{\stackrel{\wedge}{r}}_{k}(x)$ from Equation (4) to randomly generate corresponding mortality outcomes. This yields a simulated data set consisting of birthweight/mortality outcome pairs. Fitting a kcomponent normal mixture model to the simulated birthweight data and then applying PMLR to the simulated birthweight and mortality outcome data, we obtain an "estimate" of $\stackrel{\wedge}{\theta}$, which we call ${\stackrel{\wedge}{\stackrel{\wedge}{\theta}}}_{sim}$. We create four more simulated data sets in the same manner, recover the value of ${\stackrel{\wedge}{\stackrel{\wedge}{\theta}}}_{sim}$ for each, and then define ${\stackrel{\wedge}{B}}_{\theta}$ as the average value of ${\stackrel{\wedge}{\stackrel{\wedge}{\theta}}}_{sim}\stackrel{\wedge}{\theta}$ over the five simulated data sets.
A confidence interval for r _{ j }(x _{0}) is obtained by applying the inverse logit transformation to the confidence interval for θ. The above computations can be performed simultaneously at a series of birthweights. Connecting the resulting series of upper confidence limits produces an upper confidence bound for the risk function in component j, while connecting the resulting series of lower confidence limits produces a lower confidence bound.
b. Illustrative example
We continue the example from Section 2c of Results from the previous paper, involving N _{ rep }= 25 data sets of size 50,000 from the NCHS PublicUse Perinatal Mortality Data. These data sets were random samples from the aforementioned population of 202,849 white singletons whose mothers smoked heavily.
Mortality for White Singleton Infants with Heavily Smoking Mothers
Quantity  @ 1000 g  @ 2000 g  @ 3000 g  @ 4000 g 

Risk in component 1: logit^{1}{$\stackrel{\wedge}{\theta}$} [point estimate] Confidence interval  110.1 (23.2, 392.2)       
Risk in component 2: logit^{1}{$\stackrel{\wedge}{\theta}$} [point estimate] Confidence interval  460.3 (138.3, 819.2)  35.9 (16.9, 74.7)  16.2 (8.2, 31.5)  7.6 (2.3, 25.0) 
Risk in component 3: logit^{1}{$\stackrel{\wedge}{\theta}$} [point estimate] Confidence interval    41.3 (6.1, 232.1)  4.0 (0.7, 20.8)  2.4 (0.2, 29.6) 
Risk in component 4: logit^{1}{$\stackrel{\wedge}{\theta}$} [point estimate] Confidence interval      4.7 (3.0, 7.2)  2.8 (0.3, 28.3) 
Odds ratio, component 1 vs. component 2: exp{$\stackrel{\wedge}{\theta}$} [point estimate] Confidence interval  0.15 (0.01, 2.46)       
Odds ratio, component 2 vs. component 3: exp{$\stackrel{\wedge}{\theta}$} [point estimate] Confidence interval    0.87 (0.06, 12.7)  4.13 (0.41, 42.0)  3.19 (0.09, 115) 
Odds ratio, component 2 vs. component 4: exp{$\stackrel{\wedge}{\theta}$} [point estimate] Confidence interval      3.51 (1.44, 8.56)  2.74 (0.14, 53.1) 
Odds ratio, component 3 vs. component 4: exp{$\stackrel{\wedge}{\theta}$} [point estimate] Confidence interval      0.85 (0.19, 3.79)  0.86 (0.04, 21.1) 
Figure 1d reveals considerable uncertainty in estimating birthweightspecific mortality, especially in the HBW range. However, the confidence bounds for components 2 and 4 have no overlap in the lower part of the NBW range, indicating heterogeneity in mortality risk despite the uncertainty in estimation. That the confidence bounds are so wide is partly due to the large φ, which in turn is a consequence of the small population. Section 3b of Results will present another example in which the population is considerably larger and φ is much smaller.
c. Estimating odds ratios
To estimate an odds ratio comparing components in the same population, such as
odds of mortality at 1000 g in component 2 (white heavy smoking population) divided by
odds of mortality at 1000 g in component 1 (white heavy smoking population),
is a confidence interval.
To estimate an odds ratio comparing populations on the same component, such as
odds of mortality at 2500 g in component 3 (white heavy smoking population) divided by
odds of mortality at 2500 g in component 3 (white general population),
is a confidence interval. Subscripts 1 and 2 in Equation (9) identify the populations to which the "metasample" means, standard deviations, and bias adjustments pertain.
3. Further illustrations
a. Simulation study to calibrate confidence intervals
Mixture Model and Mortality Functions for Simulation Study
Model feature  Specification for simulation study 

Probability density for mixture model  .007 f(x;832,210) +.182 f(x;2772,740) +.758 f(x;3170,417) +.052 f(x;3804,413) 
Risk within component 1  r _{1}(x) = logit ^{1}(4.6975 0.2362 z + 0.3994 z ^{2} + 0.1690 z ^{3} + 0.1328 z ^{4}) 
Risk within component 2  r _{2}(x) = logit ^{1}(4.0962 0.7496 z  0.0289 z ^{2}  0.1094 z ^{3} + 0.0918 z ^{4}) 
Risk within component 3  r _{3}(x) = logit ^{1}(5.7538 1.7275 z + 1.6269 z ^{2} + 0.1897 z ^{3}  0.0249 z ^{4}) 
Risk within component 4  r _{4}(x) = logit ^{1}(5.3285 0.2786 z  0.1979 z ^{2} + 0.0535 z ^{3} + 0.0773 z ^{4}) 
Confidence Interval Coverage Probabilities in Simulation Study
C  Population Size  Bias adjustment included  Bias adjustment omitted 

Number & Percentage of Intervals Containing Targets (mortality risks)  Number & Percentage of Intervals Containing Targets (mortality risks)  
2.0  200,000  69 (57.5)  26 (21.7) 
1,000,000  92 (76.7)  26 (21.7)  
Infinite  92 (76.7)  43 (35.8)  
2.5  200,000  78 (65.0)  29 (24.2) 
1,000,000  100 (83.3)  37 (30.8)  
Infinite  96 (80.0)  47 (39.2)  
3.0  200,000  84 (70.0)  32 (26.7) 
1,000,000  106 (88.3)  44 (36.7)  
Infinite  102 (85.0)  56 (46.7)  
3.5  200,000  89 (74.2)  35 (29.2) 
1,000,000  111 (92.5)  54 (45.0)  
Infinite  110 (91.7)  60 (50.0)  
4.0  200,000  93 (77.5)  44 (36.7) 
1,000,000  116 (96.7)  63 (52.5)  
Infinite  114 (95.0)  65 (54.2)  
4.5  200,000  97 (80.8)  48 (40.0) 
1,000,000  117 (97.5)  72 (60.0)  
Infinite  115 (95.8)  76 (63.3)  
5.0  200,000  102 (85.0)  57 (47.5) 
1,000,000  117 (97.5)  79 (65.8)  
Infinite  115 (95.8)  90 (75.0) 
b. Another example with real data
Mixture Modeling Results for White Singleton Infants
Quantity  p_{1}  p_{2}  p_{3}  p_{4} 

$\stackrel{\wedge}{\theta}$ [average of 25 estimates]  .005  .117  .810  .068 
${\stackrel{\wedge}{S}}_{\theta}$ [standard deviation of 25 estimates]  .001  .010  .012  .006 
${\stackrel{\wedge}{B}}_{\theta}$ [bias adjustment]  .001  .012  .011  .007 
Confidence interval  (.004, .006)  (.099, .135)  (.792, .827)  (.058, .078) 
Quantity  μ_{1}  μ_{2}  μ_{3}  μ_{4} 
$\stackrel{\wedge}{\theta}$ [average of 25 estimates]  862  2948  3402  4056 
${\stackrel{\wedge}{S}}_{\theta}$ [standard deviation of 25 estimates]  60  52  6  18 
${\stackrel{\wedge}{B}}_{\theta}$ [bias adjustment]  22  47  4  36 
Confidence interval  (809, 915)  (2874, 3021)  (3395, 3410)  (4011, 4100) 
Quantity  σ_{1}  σ_{2}  σ_{3}  σ_{4} 
$\stackrel{\wedge}{\theta}$ [average of 25 estimates]  233  776  421  416 
${\stackrel{\wedge}{S}}_{\theta}$ [standard deviation of 25 estimates]  40  23  5  19 
${\stackrel{\wedge}{B}}_{\theta}$ [bias adjustment]  42  25  5  11 
Confidence interval  (170, 295)  (739, 813)  (413, 429)  (395, 437) 
Mortality for White Singleton Infants
Quantity  @ 1000 g  @ 2000 g  @ 3000 g  @ 4000 g 

Risk in component 1: logit^{1}{$\stackrel{\wedge}{\theta}$} [point estimate] Confidence interval  124.3 (71.1, 208.4)       
Risk in component 2: logit^{1}{$\stackrel{\wedge}{\theta}$} [point estimate] Confidence interval  242.8 (34.3, 743.1)  52.1 (41.3, 65.6)  17.0 (9.0, 31.9)  12.1 (6.6, 22.2) 
Risk in component 3: logit^{1}{$\stackrel{\wedge}{\theta}$} [point estimate] Confidence interval      1.8 (0.8, 4.1)  0.3 (0.02, 3.9) 
Risk in component 4: logit^{1}{$\stackrel{\wedge}{\theta}$} [point estimate] Confidence interval      4.2 (3.1, 5.7)  1.2 (0.4, 3.8) 
Odds ratio, component 1 vs. component 2: exp{$\stackrel{\wedge}{\theta}$} [point estimate] Confidence interval  0.44 (0.03, 6.90)       
Odds ratio, component 2 vs. component 3: exp{$\stackrel{\wedge}{\theta}$} [point estimate] Confidence interval      9.77 (2.35, 40.6)  44.3 (2.55, 768) 
Odds ratio, component 2 vs. component 4: exp{$\stackrel{\wedge}{\theta}$} [point estimate] Confidence interval      4.15 (2.04, 8.43)  10.4 (3.24, 33.6) 
Odds ratio, component 3 vs. component 4: exp{$\stackrel{\wedge}{\theta}$} [point estimate] Confidence interval      0.42 (0.18, 1.01)  0.24 (0.01, 5.34) 
The confidence intervals for p _{2}, p _{3}, μ _{2}, σ _{4} are considerably narrower than they were for white singletons born to heavilysmoking mothers, as are the confidence bounds for r _{1}(x) in the VLBW range, r _{2}(x) in the MLBW range, and r _{3}(x) in much of the NBW range. The confidence bounds for r _{2}(x) do not overlap those for r _{3}(x) or r _{4}(x) anywhere in the NBW range, indicating heterogeneity in mortality risk. In particular, the odds of mortality at 3000 g are an estimated 9.77 times as large in component 2 as in component 3 (95% confidence interval, 2.35 to 40.6) and an estimated 4.15 times as large in component 2 as in component 4 (95% confidence interval, 2.04 to 8.43).
The reason that mixture parameters and mortality risks are estimated more precisely for white singletons in general than for white singletons born to heavilysmoking mothers is that N _{ rep }= 25 samples of size 50,000 from a population of 9,162,303 contain approximately 1,171,467 distinct records, far more than the approximately 202,677 distinct records contained in N _{ rep }= 25 samples of size 50,000 from a population of 202,849. (Section II of [Additional file 1] from our previous paper provides a formula from which one may approximate the number of distinct records in multiple samples from the same population.) Even more precise estimation is possible for white singletons in general if N _{ rep }is taken larger.
Discussion
This paper completes a twopart series on a new framework for modeling birthweight distributions and fetalinfant mortality. The main advantage of this new framework is its potential to reveal heterogeneity in mortality risk that may be undetectable if one relies on a contaminated normal model or 2component normal mixture to represent a birthweight distribution.
With the contaminated normal model, the lower residual distribution and the predominant distribution have little overlap. As such, there is little overlap in the ranges of birthweights over which each component has a welldefined risk function. This is depicted in Figure 1b, where the red and green dashed curves do not occupy the same birthweights except for a small interval near 1700 g. Thus, except for birthweights close to 1700 g, the contaminated normal model effectively imposes a unique mortality risk for all infants at any fixed birthweight. This occurs because the contaminated normal model classifies all NBW cases, along with almost all MLBW and HBW cases, as originating from the predominant distribution, while it classifies virtually all VLBW and ELBW births as arising from the lower residual distribution. Yet, presumably some compromised pregnancies yield MLBW, NBW, and HBW births. Hence, not only does the estimated proportion .975 overstate the fraction of uncompromised pregnancies, but also no distinction can be made between compromised and uncompromised pregnancies at birthweights above 1700 g.
In contrast, the 2component normal mixture has some ability to reveal heterogeneity. However, this ability is limited to the MLBW, NBW, and HBW ranges. As shown in Figure 1c, the 2component normal mixture effectively imposes a unique mortality risk at each birthweight in the VLBW and ELBW ranges. At first glance, that may not seem worrisome. After all, the MLBW, NBW, and HBW cases may arise from a mix of compromised and uncompromised pregnancies, while presumably the VLBW and ELBW cases arise almost exclusively from compromised pregnancies. Yet, implicit in the 2component normal mixture is a belief that all compromised pregnancies are qualitatively similar, in the sense of sharing a common birthweightspecific mortality curve. Perhaps such a belief is approximately valid for some populations. Unfortunately, the 2component normal mixture imposes this belief mathematically and does not provide any way for it to be tested empirically. The framework that we have presented, on the other hand, allows such a belief to be tested empirically. Indeed, the example in Section 3b of Results shows that component 2 in the population of white singletons has demonstrably higher mortality risk at some birthweights than component 4 in the same population. We regard component 3 as most plausibly representing uncompromised pregnancies in this population, so that components 2 and 4 most plausibly consist of compromised pregnancies. Therefore, not all compromised pregnancies in this population share a common birthweightspecific mortality curve.
The components identified in our empirical explorations are undoubtedly related to gestational age. While detailed speculations about the precise nature of the relationship are premature, one or more of the components may have an elevated rate of intrauterine growth restriction (IUGR). Typically, IUGR is measured in populationbased vital statistics data as births below (variously) the 5th or 10th percentile of birthweight for gestational age. Other aspects not presently measured on birth certificates in the United States include head circumference at birth, birth length (i.e., crownheel length or crownrump length), and waist/hip ratio. However IUGR might be quantified, its frequency within each component could be estimated as indicated in the next paragraph.
Pursuing this idea and extending it to multiple covariates, both categorical and continuous, would enable us to describe the joint distribution of covariates within each mixture component. If the joint distributions of covariates within different mixture components had little overlap, then we would be able to assert an approximate correspondence between the mixture components and identifiable subpopulations with biological meaning. Such discoveries would provide greater epidemiologic insight into the relationships among fetalinfant mortality and its prognostic factors.
Conclusions
The present paper, the second in a twopart series, develops a new and flexible approach to modeling fetalinfant mortality through the estimation of separate birthweightspecific mortality curves within each component of a normal mixture model describing a birthweight distribution, the number of components having been determined from the data rather than fixed a priori. This approach allows the detection of heterogeneity in mortality that cannot be found with a contaminated normal model or a 2component normal mixture model. A 2component normal mixture model assumes that infants from compromised pregnancies share a common birthweightspecific mortality curve, while a contaminated normal model assumes that all infants share a common curve over some (possibly quite large) interval of birthweights. Yet, our approach has demonstrated that components 2 and 4 in a 4component normal mixture model for white singleton birthweights have distinct birthweightspecific mortality curves. Since components 2 and 4 in this population most plausibly consist of compromised pregnancies, we see that infants from compromised pregnancies need not share a common birthweightspecific mortality curve. Finally, this paper lays some groundwork for future research aimed at discovering approximate correspondences between mixture model components and identifiable subpopulations.
Methods
[Additional file 1] presents technical details on our methodology and its implementation.
Abbreviations
 ELBW:

extremely low birthweight
 FLIC:

Flexible Information Criterion
 HBW:

high birthweight
 IUGR:

intrauterine growth restriction
 MLBW:

moderately low birthweight
 NBW:

normal birthweight
 NCHS:

National Center for Health Statistics
 PMLR:

parametric mixtures of logistic regressions
 VLBW:

very low birthweight
Declarations
Acknowledgements
The authors thank Vicki Flenady, Gerald Hoff, and an anonymous Associate Editor for feedback that led to improvement of this manuscript.
Authors’ Affiliations
References
 Hamilton BE, Martin JA, Ventura SJ, Births : Preliminary Data for 2007. National Vital Statistics Reports. 2009, 57: 123.Google Scholar
 Brimblecombe F, Ashford J, Fryer J: Significance of Low Birth Weight in Perinatal Mortality: A Study of Variations within England and Wales. Br J Prev Soc Med. 1968, 22: 2735.PubMedPubMed CentralGoogle Scholar
 Kiely JL, Kleinman JC: BirthWeightAdjusted Infant Mortality in Evaluations of Perinatal Care: Towards a Useful Summary Measure. Stat Med. 1993, 12: 377392. 10.1002/sim.4780120319.View ArticlePubMedGoogle Scholar
 Russell RB, Green NS, Steiner CA, Meikle S, Howse JL, Poschman K, Dias T, Potetz L, Davidoff MJ, Damus K, Petrini JR: Cost of Hospitalization for Preterm and Low Birth Weight Infants in the United States. Pediatrics. 2007, 120: 19. 10.1542/peds.20062386.View ArticleGoogle Scholar
 Umbach D, Wilcox AJ: A Technique for Measuring Epidemiologically Useful Features of Birthweight Distributions. Stat Med. 1996, 15: 13331348. 10.1002/(SICI)10970258(19960715)15:13<1333::AIDSIM271>3.0.CO;2R.View ArticlePubMedGoogle Scholar
 Gage T, Therriault G: Variability of BirthWeight Distributions by Sex and Ethnicity: Analysis Using Mixture Models. Hum Biol. 1998, 70: 517534.PubMedGoogle Scholar
 Gage T: BirthWeightSpecific Infant and Neonatal Mortality: Effects of Heterogeneity in the Birth Cohort. Hum Biol. 2002, 74: 165184. 10.1353/hub.2002.0020.View ArticlePubMedGoogle Scholar
 Casella G, Berger R: Statistical Inference. 2002, Duxbury, Pacific Grove, 2Google Scholar
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