Omics data integration is already a reality. However, few omics-based algorithms show enough predictive ability to be implemented into clinics or public health domains. Clinical/epidemiological data tend to explain most of the variation of health-related traits, and its joint modeling with omics data is crucial to increase the algorithm’s predictive ability. Only a small number of published studies performed a “real” integration of omics and non-omics (OnO) data, mainly to predict cancer outcomes. Challenges in OnO data integration regard the nature and heterogeneity of non-omics data, the possibility of integrating large-scale non-omics data with high-throughput omics data, the relationship between OnO data (i.e., ascertainment bias), the presence of interactions, the fairness of the models, and the presence of subphenotypes. These challenges demand the development and application of new analysis strategies to integrate OnO data. In this contribution we discuss different attempts of OnO data integration in clinical and epidemiological studies. Most of the reviewed papers considered only one type of omics data set, mainly RNA expression data. All selected papers incorporated non-omics data in a low-dimensionality fashion. The integrative strategies used in the identified papers adopted three modeling methods: Independent, conditional, and joint modeling. This review presents, discusses, and proposes integrative analytical strategies towards OnO data integration.

Inbreeding depression on female fertility and calving ease in Spanish dairy cattle was studied by the traditional inbreeding coefficient (F) and an alternative measurement indicating the inbreeding rate (DeltaF) for each animal. Data included records from 49,497 and 62,134 cows for fertility and calving ease, respectively. Both inbreeding measurements were included separately in the routine genetic evaluation models for number of insemination to conception (sequential threshold animal model) and calving ease (sire-maternal grandsire threshold model). The F was included in the model as a categorical effect, whereas DeltaF was included as a linear covariate. Inbred cows showed impaired fertility and tended to have more difficult calvings than low or noninbred cows. Pregnancy rate decreased by 1.68% on average for cows with F from 6.25 to 12.5%. This amount of inbreeding, however, did not seem to increase dystocia incidence. Inbreeding depression was larger for F greater than 12.5%. Cows with F greater than 25% had lower pregnancy rate and higher dystocia rate (-6.37 and 1.67%, respectively) than low or noninbred cows. The DeltaF had a significant effect on female fertility. A DeltaF = 0.01, corresponding to an inbreeding coefficient of 5.62% for the average equivalent generations in the data used (5.68), lowered pregnancy rate by 1.5%. However, the posterior estimate for the effect of DeltaF on calving ease was not significantly different from zero. Although similar patterns were found with both F and DeltaF, the latter detected a lowered pregnancy rate at an equivalent F, probably because it may consider the known depth of the pedigree. The inbreeding rate might be an alternative choice to measure inbreeding depression.

The use of structural equation models for the analysis of recursive and simultaneous relationships between phenotypes has become more popular recently. The aim of this paper is to illustrate how these models can be applied in animal breeding to achieve parameterizations of different levels of complexity and, more specifically, to model phenotypic recursion between three calving traits: gestation length (GL), calving difficulty (CD) and stillbirth (SB). All recursive models considered here postulate heterogeneous recursive relationships between GL and liabilities to CD and SB, and between liability to CD and liability to SB, depending on categories of GL phenotype.

A method based on the analysis of recursive multiple-trait models was used to 1) estimate genetic and phenotypic relationships of calving ease (CE) with fertility traits and 2) analyze whether dystocia negatively affects reproductive performance in the next reproductive cycle. Data were collected from 1995 through 2002, and contained 33,532 records of CE and reproductive data of 17,558 Holstein cows distributed across 560 herds in official milk recording from the Basque Country Autonomous Community (Spain). The following fertility traits were considered: days open (DO), days to first service, number of services per pregnancy (NINS), and outcome of first insemination (OFI). Four bivariate sire and sire-maternal grandsire models were used for the analyses. Censoring existed in DO (26.49% of the data) and NINS (12.22% of the data) because of cows having been sold or culled before reaching the next parturition. To avoid bias, a data augmentation technique was applied to censored data. Threshold models were used for CE and OFI. To consider that CE affects fertility and the genetic determination of CE and fertility traits, recursive models were applied, which simultaneously considered CE as a fixed effect on fertility performance and the existence of a genetic correlation between CE and fertility traits. The effects of CE score 3 (difficult birth) with respect to score 1 (no problem) for days to first service, DO, NINS, and OFI were 8 d, 31 d, 0.5 services, and -12% success at first insemination, respectively. These results showed poorer fertility after dystocia. Genetic correlations between genetic effects of fertility traits and CE were close to zero, except for the genetic correlations between direct effects of DO and CE, which were positive, moderate, and statistically different from 0 (0.47 +/- 0.24), showing that genes associated with difficult births also reduce reproductive success.

Structural equation models (SEMs) of a recursive type with heterogeneous structural coefficients were used to explore biological relationships between gestation length (GL), calving difficulty (CD), and perinatal mortality, also known as stillbirth (SB), in cattle, with the last two traits having categorical expression. An acyclic model was assumed, where recursive effects existed from the GL phenotype to the liabilities (latent variables) to CD and SB and from the liability to CD to that of SB considering four periods regarding GL. The data contained GL, CD, and SB records from 90,393 primiparous cows, sired by 1122 bulls, distributed over 935 herd-calving year classes. Low genetic correlations between GL and the other calving traits were found, whereas the liabilities to CD and SB were high and positively correlated, genetically. The model indicated that gestations of ∼274 days of length (3 days shorter than the average) would lead to the lowest CD and SB and confirmed the existence of an intermediate optimum of GL with respect to these traits.