t To evaluate the accuracy of detecting 16 year old male (N=465) and female (N=162) youths who subsequently manifest opioid use disorder (OUD) at 25 years of age. We hypothesized that the combined measures of two components of etiology, heritable risk and substance use, accurately detect youths who develop OUD.

Heritable risk was measured by the transmissible liability index (TLI). Severity of the prodrome presaging OUD was quantified by the revised Drug Use Screening Inventory (DUSI-R) containing the consumption frequency index (CFI) documenting substance use events during the past month and the overall problem density (OPD) score indicating co-occurring biopsychosocial problems. Diagnosis of OUD was formulated by a clinical committee based on results of the Structured Clinical Interview for DSM-IV in conjunction with medical and social history records.

Bivariate analysis shows that the TLI, CFI, and OPD scores at 16 years of age predict OUD at 25 years. Multivariate modeling indicates that the TLI combined with the CFI predict OUD with 86% accuracy (sensitivity = 87%; specificity = 62%). The TLI and CFI at 16 years of age mediate the association between parental substance use disorder and OUD in offspring at 25 years of age, indicating that these measures respectively evaluate risk and prodrome.

These results demonstrate the feasibility of identifying youths requiring intervention to prevent OUD.

Over 11,000,000 Americans misused prescription opioids in 2017 (

The present longitudinal investigation examined the accuracy of forecasting
opioid use disorder (OUD) manifest at 25 years of age based on measurement of two main
etiological components, heritable liability (

Participants were recruited by the Center for Education and Drug Abuse
Research (CEDAR), a NIDA-funded longitudinal study of substance use disorder
etiology (

Attrition between baseline (age 16) and outcome (age 25) assessments was 33%
in boys and 17% in girls. The most frequent reasons for attrition were relocation
(including military service and incarceration) and inability to contact the
participant despite deploying a comprehensive tracking protocol. Notably, the
attrited and retained segments of the male sample do not differ on the TLI, CFI and
OPD predictor variables. The CFI score was, however, higher among girls who
attrited. Rate of substance use disorder in parents, as shown in

Diagnostic formulation of the parents and their children was
conducted using the

Number of parents (0, 1, 2) with substance use disorder was recorded
to measure magnitude of familial loading for this disorder in their
children. This indicator of intergenerational risk has been shown in prior
research to be heuristic for elucidating the risk for and developmental
patterning to substance use disorder (

Previous reports describe the theory (

The self-administered DUSI-R measures severity of problems pertaining to: 1) substance use, 2) mental health, 3) physical health, 4) behavior self-regulation, 5) school adjustment, 6) family functioning, 7) peer relationships, 8) social skills, 9) work adjustment and 10) leisure/recreation activities. The overall problem density (OPD) score is computed by dividing the number of items in which a problem is endorsed by the total number of items encompassing the ten scales (N=149) and then multiplying the resultant quotient by 100. The overall problem density (OPD) score thus has a range of 0–100%. The mean OPD scores in the samples of boys and girls are 18.5% and 20.4%.

Convincing evidence demonstrates that liabilities to all substance
use disorder categories share to large extent genetic and phenotypic
variance (

At baseline (age 16), only 6% of the sample reported lifetime opioid use, whereas 24% of the sample used opioids at least once by age 25. By age 25 (outcome), OUD was present in 6.4% of the sample (6.2% males; 6.7% females); however, information was not available regarding whether the first opioid used was a medicine prescribed by a physician, was self-directed, or involved a Schedule I substance.

After orientation to the laboratory the parents and their children
respectively signed the informed consent and assent forms approved by the
University of Pittsburgh IRB. Privacy was additionally assured by a

Analyses were conducted at the outset to confirm that the TLI and CFI/OPD are respectively valid measures of transmissible risk and OUD prodrome. Polyserial correlation evaluated the relationship between the participant’s familial loading of substance use disorder (i.e., number of affected parents) and TLI score. Point-biserial correlation estimated the association between TLI, CFI and OPD scores and OUD.

Next, multi-sample path analysis was conducted to model the
relationships between number of affected parents and their children’s
TLI, CFI, and OPD scores at 16 years of age, and OUD at 25 years of age. Three
models were compared. Model 1 assumed that all path (standardized partial
regression) coefficients, means, and variances are equal between boys and girls.
Model 2 assumed that only the path coefficients are equal. Model 3 assumed that
all parameters are free. Path coefficients were estimated using Mplus (^{2}
goodness-of-fit index, 2) root mean square error of approximation (RMSEA), 3)
comparative fit index, and 4) Tucker-Lewis index. Nonsignificant
χ^{2}, RMSEA below 0.05, and comparative fit and Tucker-Lewis
indexes close to 1 indicate good fit. Fit comparisons between the nested models
(differing in that the parameters in the more general model are equated or
absent from another model) are conducted using the difference of
χ^{2} values between the models. This statistic has an
asymptotic χ^{2} distribution with the degrees of freedoms equal
to the difference between the degrees of freedom of the models. Mediation
analyses were conducted employing the method described by Sobel (

As can be seen in

^{2}=17.12, df=17, p=.42). Whereas both models
are statistically acceptable, we adopted Model 1 because it allows including
females in the analysis that would not be otherwise possible with Model 3 due to
the relatively small subset who developed OUD.

As indicated by the path coefficients (

TLI mediates the association between number of parents with substance use disorder and OUD outcome in their children (β = 0.10, z=4.62, p<.001). In effect, familial loading for substance use disorder covaries with TLI score quantifying transmissible liability. In addition, CFI mediates the relationship between number of substance use disorder parents and their children’s OUD diagnosis (β = 0.03, z=2.83, p=.005). This finding demonstrates that the CFI is a valid measure of the OUD prodrome and related to magnitude of intergenerational risk.

To evaluate the utility of the predictors for forecasting OUD while
taking into account their correlations, we applied the parameters obtained in
path analysis to a logistic regression model. The respective odds ratios for the
TLI and CFI are respectively 1.47 (95% CI: 1.30–1.66) and 1.83 (95% CI:
1.07–1.31). As shown in

Cost-efficient prevention of OUD is contingent on identifying the high-risk
segment in the general population. The polygenic risk score, aggregating information
on genetic polymorphisms identified in genome-wide association studies (

Results obtained in other studies also demonstrate that it is feasible to
predict OUD (

In addition, it is noteworthy that the TLI includes indicators of social
deviancy. This is important considering that opioid users often violate the law by
consuming medicinal opioids without physician prescription or using Schedule I
formulations. Notably, severity of externalizing disorder in childhood covaries with
magnitude of risk for developing opioid dependence in adulthood (

Recent survey data indicate that approximately 22.3 million Americans are in
recovery from substance misuse, within which 5% report that opioids were the main
problem (

Several caveats and limitations of this study are noted. Whereas the results
lend confidence to the feasibility of routine risk screening, it should be noted
that although sensitivity is high (87%), specificity is somewhat low for the total
sample. A k-fold cross-validation provided somewhat different results: sensitivity
was 75% and specificity was 89% with similar cut-off scores. In effect, false
positive rate is 38% for the total sample, whereas it is 11% for the 5-fold
cross-validation. In the light of differences we observed in sensitivity and
specificity between the total and cross-validation samples, the generalizability of
the predictive model for new samples should be interpreted with care. In particular,
caution must be exercised before denying intervention based solely on the results of
this assessment. Even though a false-positive conclusion regarding OUD prediction is
less costly than non-detection of a true-positive case, further research focusing on
improving measurement precision is required, particularly directed at youth in the
low-risk area of the liability distribution (

In summary, the index of transmissible liability to substance use disorder combined with past 30-day frequency of overall substance use detects 16-year old youths who qualify for OUD at 25 years of age with 86% accuracy. Considering that this assessment can be self-administered on the Web platform, currently under development, this protocol may be useful for large scale or routine screening to detect high-risk youths requiring prevention intervention.

Supported by the National Institute of Drug Abuse (P50 DA005605), Center for Disease Control (R01 CE002996), and NIDA (UG1 DA049444). The authors declare no conflicts of interest.

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Path model depicting the relationship among parental substance use disorder (SUD), child’s transmissible liability index (TLI), consumption frequency index (CFI), and overall problem density (OPD) score at 16 years of age on current opioid use disorder (OUD) diagnosis at 25 years of age).

Characteristics of the sample at 16 years of age who were retained or attrited at 25 years of age

Male | Female | |||||
---|---|---|---|---|---|---|

Retained | Attrited | Test Statistics | Retained | Attrited | Test Statistics | |

SUD in father (probands) | 49% | 56% | χ^{2}=.06,p=.81 | 41% | 52% | χ^{2}=.35,p=55 |

SUD in mother | 20% | 26% | χ^{2}=.07,p=79 | 20% | 39% | χ^{2}=2.66,p=.10 |

IQ (Mean, SD) | 108.7(15.3) | 106.3 (16.5) | t=2.61,p=.01 | 104.8(17.2) | 100.7 (14.4) | t=2.43,p=.02 |

Family SES (Mean, SD) | 41.4(13.2) | 40.8(13.6) | t=1.50,p=.13 | 42.7 (14.7) | 41.0(16.1) | t=1.60,p=.14 |

Ethnicity | ||||||

• Euro-American | 77% | 78% | χ^{2}=.98,p=32 | 67% | 59% | χ^{2}=.08,p=78 |

• African American | 23% | 22% | 33% | 41% | ||

Transmissible Liability | .05(1.01) | .12(1.06) | t=−.57, p=.56 | −.23 (.97) | .04 (.87) | t=−1.04, p=.29 |

Index (TLI) (z score) | ||||||

Consumption Frequency | 1.86(2.34) | 2.16(2.43) | t=−1.52,p=.13 | 1.52(1.95) | 2.50 (2.34) | t=−2.79, p=.006 |

Index (CFI)^{1} | ||||||

Overall Problem Density | 18.52(12.79) | 16.28 (12.34) | t=1.58, p=.ll | 20.38(12.85) | 21.99(13.37) | t=−.48, p=.63 |

Score (OPD) (%)^{2} |

Consumption events in past month

Score ranges from 0–10

Bivariate correlations among number of substance use disorder (SUD) parents and child’s transmissible liability index (TLI), overall problem density score (OPD), consumption frequency index (CFI) and opioid use disorder (OUD)

TLI | OPD | CFI | OUD | ||
---|---|---|---|---|---|

r (p-value) | r (p-value) | r (p-value) | r (p-value) | ||

Boys | SUD Parents | .32 (<.001) | .27 (<.001) | .25 (<.001) | .10 (.06) |

TLI | .74 (<.001) | .46 (<.001) | .32 (<.001) | ||

OPD | .53 (<.001) | .36 (p<.001) | |||

CFI | .34 (p<.001) | ||||

Girls | SUD Parents | .24 (.004) | .36(<.001) | .24 (.002) | .08 (.32) |

TLI | .70 (<.001) | .24 (.008) | .20 (.03) | ||

OPD | .40 (<.001) | .21 (.01) | |||

CFI | .25 (.006) |

Fit statistics of path models

Model | χ^{2} | df | P | RMSEA | Comparative fit index | Tucker-Lewis Index |
---|---|---|---|---|---|---|

1 | 17.58 | 19 | .55 | <.001 | .99 | .99 |

2 | 14.75 | 11 | .19 | .032 | .99 | .98 |

3 | 0.46 | 2 | .79 | <001 | .99 | .99 |

Note: Model 1 assumed that all path coefficients, means and variances are equal between boys and girls. Model 2 assumed that only the path coefficients are equal. Model 3 assumed that all parameters are free.

Logistic regression analysis for predicting opioid use disorder at age 25 by TLI and CFI

B | SE | OR | p-values | 95% CI | |
---|---|---|---|---|---|

TLI | .39 | .06 | 1.47 | <.001 | 1.30, 1.66 |

CFI | .17 | .05 | 1.18 | <.001 | 1.07, 1.31 |

Results of ROC analyses based on total sample and 5-fold cross validation

AUC | Sensitivity | Specificity | Cut-off score | |
---|---|---|---|---|

Total sample | 86% | 87% | 62% | 5.5% |

Average across 5 folds | 89% | 75% | 89% | 6% |