Historical controls in clinical trials: a note on linking Pocock's model with the robust mixture priors.

Several Bayesian methods have been proposed to borrow information dynamically from historical controls in clinical trials. In this note, we identify key features of the relationship between the first method proposed, the bias-variance method, which is strongly related to the commensurate prior approach, and a more recent and widely used approach called robust mixture priors (RMP). We focus on the two key terms that need to be chosen to define the RMP, namely $w$, the prior probability that the new trial differs systematically from the historical trial, and $s_v^2$, the variance of the vague component of the RMP. The relationship with Pocock's prior reveals that different combinations of these two terms can express similar prior beliefs about the amount of information provided by the historical data. This demonstrates the value of fixing $s_v^2$, e.g., so the vague component is "worth one subject." Prior belief about the relevance of the historical data is then driven by a single value, the prespecified weight $w$.

An information-theoretic approach for the assessment of a continuous outcome as a surrogate for a binary true endpoint based on causal inference: Application to vaccine evaluation.

Within the causal association paradigm, a method is proposed to assess the validity of a continuous outcome as a surrogate for a binary true endpoint. The methodology is based on a previously introduced information-theoretic definition of surrogacy and has two main steps. In the first step, a new model is proposed to describe the joint distribution of the potential outcomes associated with the putative surrogate and the true endpoint of interest. The identifiability issues inherent to this type of models are handled via sensitivity analysis. In the second step, a metric of surrogacy new to this setting, the so-called individual causal association is presented. The methodology is studied in detail using theoretical considerations, some simulations, and data from a randomized clinical trial evaluating an inactivated quadrivalent influenza vaccine. A user-friendly R package Surrogate is provided to carry out the evaluation exercise.

Dynamic borrowing of historical controls adjusting for covariates in vaccine efficacy clinical trials.

Traditional vaccine efficacy trials usually use fixed designs and often require large sample sizes. Recruiting a large number of subjects can make the trial expensive, long, and difficult to conduct. A possible approach to reduce the sample size and speed up the development is to use historical controls. In this paper, we extend the robust mixture prior (RMP) approach (a well established approach for Bayesian dynamic borrowing of historical controls) to adjust for covariates. The adjustment is done using classical methods from causal inference: inverse probability of treatment weighting, G-computation and double-robust estimation. We evaluate these covariate-adjusted RMP approaches using a comprehensive simulation study and demonstrate their use by performing a retrospective analysis of a prophylactic human papillomavirus vaccine efficacy trial. Adjusting for covariates reduces the drift between current and historical controls, with a beneficial effect on bias, control of type I error and power.

Vaccine clinical trials with dynamic borrowing of historical controls: Two retrospective studies.

Traditional vaccine efficacy trials usually use fixed designs with fairly large sample sizes. Recruiting a large number of subjects requires longer time and higher costs. Furthermore, vaccine developers are more than ever facing the need to accelerate vaccine development to fulfill the public's medical needs. A possible approach to accelerate development is to use the method of dynamic borrowing of historical controls in clinical trials. In this paper, we evaluate the feasibility and the performance of this approach in vaccine development by retrospectively analyzing two real vaccine studies: a relatively small immunological trial (typical early phase study) and a large vaccine efficacy trial (typical Phase 3 study) assessing prophylactic human papillomavirus vaccine. Results are promising, particularly for early development immunological studies, where the adaptive design is feasible, and control of type I error is less relevant.

Association Between Immunogenicity and Reactogenicity: A Post Hoc Analysis of 2 Phase 3 Studies With the Adjuvanted Recombinant Zoster Vaccine.

A recurrent question is whether transient reactions to vaccines translate into better immune responses. Using clinical data from 2 large phase 3 studies of the recombinant zoster vaccine, we observed a small but statistically significant association between the intensity of a frequent side effect (pain) after vaccination and immune responses to vaccination. However, despite the statistical correlation, the impact on the immune response is so small, and the immune response in individuals without pain already sufficient, that pain cannot be a surrogate marker for an appropriate immune response. Reactogenicity cannot be used to predict immunity after vaccination.

Assurance in vaccine efficacy clinical trial design based on immunological responses.

The assurance of a future clinical trial is a key quantitative tool for decision-making in drug development. It is derived from prior knowledge (Bayesian approach) about the clinical endpoint of interest, typically from previous clinical trials. In this paper, we examine assurance in the specific context of vaccine development, where early development (Phase 2) is often based on immunological endpoints (e.g., antibody levels), while the confirmatory trial (Phase 3) is based on the clinical endpoint (very large sample sizes and long follow-up). Our proposal is to use the Phase 2 vaccine efficacy predicted by the immunological endpoint (using a model estimated from epidemiological studies) as prior information for the calculation of the assurance.

Burden-of-illness vaccine efficacy.

In recent years, many vaccines have been developed for the prevention of a variety of diseases. Although the primary objective of vaccination is to prevent disease, vaccination can also reduce the severity of disease in those individuals who develop breakthrough disease. Observations of apparent mitigation of breakthrough disease in vaccine recipients have been reported for a number of vaccine-preventable diseases such as Herpes Zoster, Influenza, Rotavirus, and Pertussis. The burden-of-illness (BOI) score was developed to incorporate the incidence of disease as well as the severity and duration of disease. A severity-of-illness score S > 0 is assigned to individuals who develop disease and a score of 0 is assigned to uninfected individuals. In this article, we derive the vaccine efficacy statistic (which is the standard statistic for presenting efficacy outcomes in vaccine clinical trials) based on BOI scores, and we extend the method to adjust for baseline covariates. Also, we illustrate it with data from a clinical trial in which the efficacy of a Herpes Zoster vaccine was evaluated.

Assessing correlates of protection in vaccine trials: statistical solutions in the context of high vaccine efficacy.

BACKGROUND: The use of correlates of protection (CoPs) in vaccination trials offers significant advantages as useful clinical endpoint substitutes. Vaccines with very high vaccine efficacy (VE) are documented in the literature (VE ≥95%). The rare events (number of infections) observed in the vaccinated groups of these trials posed challenges when applying conventionally-used statistical methods for CoP assessment. In this paper, we describe the nature of these challenges, and propose easy-to-implement and uniquely-tailored statistical solutions for the assessment of CoPs in the specific context of high VE. METHODS: The Prentice criteria and meta-analytic frameworks are standard statistical methods for assessing vaccine CoPs, but can be problematic in high VE cases due to the rare events data available. As a result, lack of fit and the problem of infinite estimates may arise, in the former and latter methods respectively. The use of flexible models within the Prentice framework, and penalized-likelihood methods to solve the issue of infinite estimates can improve the performance of both methods in high VE settings. RESULTS: We have 1) devised flexible non-linear models to counteract the Prentice framework lack of fit, providing sufficient statistical power to the method, and 2) proposed the use of penalised likelihood approaches to make the meta-analytic framework applicable on randomized subgroups, such as regions. The performance of the proposed methods for high VE cases was evaluated by running simulations. CONCLUSIONS: As vaccines with high efficacy are documented in the literature, there is a need to identify effective statistical solutions to assess CoPs. Our proposed adaptations are straight-forward and improve the performance of conventional statistical methods for high VE data, leading to more reliable CoP assessments in the context of high VE settings.

A note on tests for relevant differences with extremely large sample sizes.

A well-known problem in classical two-tailed hypothesis testing is that P-values go to zero when the sample size goes to infinity, irrespectively of the effect size. This pitfall can make the testing of data consisting of large sample sizes potentially unreliable. In this note, we propose to test for relevant differences to overcome this issue. We illustrate the proposed test a on real data set of about 40 million privately insured patients.

MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting. METHODS: DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 µg MAGE-A3 antigen plus 420 µg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT00796445. FINDINGS: Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28·0 months [IQR 23·3-35·5] in the MAGE-A3 group and 28·1 months [23·7-36·9] in the placebo group. Median disease-free survival was 11·0 months (95% CI 10·0-11·9) in the MAGE-A3 group and 11·2 months (8·6-14·1) in the placebo group (hazard ratio [HR] 1·01, 0·88-1·17, p=0·86). In the GS-positive population, median disease-free survival was 9·9 months (95% CI 5·7-17·6) in the MAGE-A3 group and 11·6 months (5·6-22·3) in the placebo group (HR 1·11, 0·83-1·49, p=0·48). Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 [3%] for MAGE-A3 vs four [<1%] for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment. INTERPRETATION: An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped. FUNDING: GlaxoSmithKline Biologicals SA.

Testing interaction between treatment and high-dimensional covariates in randomized clinical trials.

In this paper, we considered different methods to test the interaction between treatment and a potentially large number (p) of covariates in randomized clinical trials. The simplest approach was to fit univariate (marginal) models and to combine the univariate statistics or p-values (e.g., minimum p-value). Another possibility was to reduce the dimension of the covariates using the principal components (PCs) and to test the interaction between treatment and PCs. Finally, we considered the Goeman global test applied to the high-dimensional interaction matrix, adjusted for the main (treatment and covariates) effects. These tests can be used for personalized medicine to test if a large set of biomarkers can be useful to identify a subset of patients who may be more responsive to treatment. We evaluated the performance of these methods on simulated data and we applied them on data from two early phases oncology clinical trials.

A phase I/II trial of the safety and clinical activity of a HER2-protein based immunotherapeutic for treating women with HER2-positive metastatic breast cancer.

The objectives of this phase I/II study (NCT00140738) were to evaluate the safety and clinical activity of a cancer immunotherapeutic agent (recombinant HER2 protein (dHER2) and the immunostimulant AS15) in patients with HER2-overexpressing metastatic breast cancer (MBC). Forty HER2-positive MBC patients received up to 18 doses (12q2w, 6q3w) of dHER2 immunotherapeutic, as first- or second-line therapy following response to trastuzumab-based treatment as maintenance. Toxicity was graded by the Common Terminology Criteria for Adverse Events (CTCAE) and clinical activity was evaluated by target lesion assessment according to the Response Evaluation Criteria in Solid Tumors (RECIST). Immunogenicity was assessed. The dHER2 immunotherapeutic was well tolerated: grade 1/2 adverse events (AEs) were most common. No cardiac events were observed and one patient experienced an asymptomatic decrease of left ventricular ejection fraction below the normal range (47 %). Both humoral and cellular immunogenicity to the dHER2 antigen was observed. No patient discontinued the immunizations because of AEs but 35/40 withdrew prematurely, 34 because of disease progression (24/34 before or at the tumor assessment after dose 6). One patient achieved a complete response lasting 11 months and one patient had a partial response lasting 3.5 months. Ten patients experienced stable disease ≥26 weeks with 4/10 still in stable disease at the last tumor assessment after 47 weeks. Immunization of MBC patients with the dHER2 immunotherapeutic was associated with minimal toxicity and no cardiac events. Clinical activity was observed with two objective responses and prolonged stable disease for 10/40 patients.

A non-randomized dose-escalation Phase I trial of a protein-based immunotherapeutic for the treatment of breast cancer patients with HER2-overexpressing tumors.

This Phase I dose-escalation study (NCT00058526) assessed the safety and immunogenicity of an anti-cancer immunotherapeutic (recombinant HER2 protein (dHER2) combined with the immunostimulant AS15) in patients with early-stage HER2-overexpressing breast cancer (BC). Sixty-one trastuzumab-naive patients with stage II-III HER2-positive BC received the dHER2 immunotherapeutic after surgical resection and adjuvant therapy. They were allocated into four cohorts receiving different doses of dHER2 (20, 100, 500 µg) combined with a fixed AS15 dose. Safety and immunogenicity (dHER2-specific antibody responses) were assessed. After completing the immunization schedule (three or six doses over 14 weeks) and a six-month follow-up, the patients were followed for 5 years for late toxicity, long-term immunogenicity, and clinical status. The immunizations were well tolerated, and increasing doses of dHER2 had no impact on the frequency or severity of adverse events. Few late toxicities were reported, and after 5 years 45/54 patients (83.3 %) were still alive, while 28/45 (62 %) with known disease status were disease free. Regarding the immunogenicity of the compound, a positive association was found between the dHER2 dose, the immunization schedule, and the prevalence of dHER2-specific humoral responses. Among the patients receiving the most intense immunization schedule with the highest dHER2 dose, 6/8 maintained their dHER2-specific antibody response 5 years after immunization. The dHER2 immunotherapeutic had an acceptable safety profile in early HER2-positive BC patients. dHER2-specific antibody responses were induced, with the rate of responders increasing with the dHER2 dose and the number and frequency of immunizations.

A predictive enrichment procedure to identify potential responders to a new therapy for randomized, comparative controlled clinical studies.

To evaluate a new therapy versus a control via a randomized, comparative clinical study or a series of trials, due to heterogeneity of the study patient population, a pre-specified, predictive enrichment procedure may be implemented to identify an "enrichable" subpopulation. For patients in this subpopulation, the therapy is expected to have a desirable overall risk-benefit profile. To develop and validate such a "therapy-diagnostic co-development" strategy, a three-step procedure may be conducted with three independent data sets from a series of similar studies or a single trial. At the first stage, we create various candidate scoring systems based on the baseline information of the patients via, for example, parametric models using the first data set. Each individual score reflects an anticipated average treatment difference for future patients who share similar baseline profiles. A large score indicates that these patients tend to benefit from the new therapy. At the second step, a potentially promising, enrichable subgroup is identified using the totality of evidence from these scoring systems. At the final stage, we validate such a selection via two-sample inference procedures for assessing the treatment effectiveness statistically and clinically with the third data set, the so-called holdout sample. When the study size is not large, one may combine the first two steps using a "cross-training-evaluation" process. Comprehensive numerical studies are conducted to investigate the operational characteristics of the proposed method. The entire enrichment procedure is illustrated with the data from a cardiovascular trial to evaluate a beta-blocker versus a placebo for treating chronic heart failure patients.

Putative correlates of protection against shigellosis assessing immunomarkers across responses to S. sonnei investigational vaccine.

Shigella spp. are a leading bacterial cause of diarrhea. No widely licensed vaccines are available and there is no generally accepted correlate of protection. We tested a S. sonnei Generalized Modules for Membrane Antigen (GMMA)-based vaccine (1790GAHB) in a phase 2b, placebo-controlled, randomized, controlled human infection model study (NCT03527173) enrolling healthy United States adults aged 18-50 years. We report analyses evaluating immune responses to vaccination, with the aim to identify correlates of risk for shigellosis among assessed immunomarkers. We found that 1790GAHB elicited S. sonnei lipopolysaccharide specific α4ß7+ immunoglobulin (Ig) G and IgA secreting B cells which are likely homing to the gut, indicating the ability to induce a mucosal in addition to a systemic response, despite parenteral delivery. We were unable to establish or confirm threshold levels that predict vaccine efficacy facilitating the evaluation of vaccine candidates. However, serum anti-lipopolysaccharide IgG and bactericidal activity were identified as potential correlates of risk for shigellosis.

Effectiveness of maternal immunisation with a three-component acellular pertussis vaccine at preventing pertussis in infants in the United States: Post-hoc analysis of a case-control study using Bayesian dynamic borrowing.

BACKGROUND: Immunisation during pregnancy with a tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine can protect infants against pertussis between birth and paediatric vaccination. We aimed to estimate the vaccine effectiveness (VE) of third-trimester pregnancy immunisation with the three-component acellular pertussis (Td3ap) vaccine at preventing pertussis in infants <2 months in the United States (US), to support a label update. METHODS: We performed a post-hoc sub-analysis of a case-control study conducted in six US Emerging Infections Program Network states between 2011 and 2014. Our analysis included only cases and controls whose mothers were either vaccinated with Td3ap or did not receive any Tdap vaccine. The association between Td3ap maternal immunisation and pertussis in infants was assessed for US data using a frequentist method with conditional logistic regression. A robustified analysis was conducted using Bayesian dynamic borrowing of non-US data, considering a mixing-weighted prior of 90% for historical non-US VE data, and of 10% for a vague prior. VE was estimated as (1-odds ratio) × 100%. Sensitivity analyses accounting for the impact of each non-US study, different mixing weights and missing/ambiguous data were performed. RESULTS: We included 108 cases and 183 controls. Based on US data, the estimated VE of third-trimester maternal immunisation with Td3ap at preventing pertussis in infants <2 months was 78.0% (95% confidence interval: -38.0; 96.5). VE estimated by Bayesian dynamic borrowing of non-US data (with a 90% weight for historical data) was 83.4% (95% credible interval: 55.7; 92.5); sensitivity analyses produced similar VE estimates. CONCLUSIONS: Effectiveness of third-trimester pregnancy immunisation with Td3ap at preventing infant pertussis in the US is very likely to be ≥ 50% and is most likely âˆ¼ 80%. Bayesian dynamic borrowing of non-US VE data allowed overcoming the limited power (due to small sample size) of a brand-specific sub-analysis by considering additional evidence.

Meta-Regression of Herpes Zoster Incidence Worldwide.

INTRODUCTION: Many studies have been conducted worldwide to estimate herpes zoster (HZ) incidence rates. We synthesized studies of HZ incidence rates in the general population using meta-analysis models. METHODS: A random effects meta-analysis was conducted to estimate HZ incidence from a published worldwide systematic literature review (SLR) including only individuals aged 50 years and older. Meta-regression was used to explore whether variability in incidence rates could be explained by a combination of study-specific characteristics including age, gender, continent and year of study data. The impact of adding additional covariates-case detection method (general practitioner surveillance, healthcare database, sentinel network, etc.), case definition (medical record-based, self-reported), study design (retrospective passive surveillance, retrospective active surveillance, etc.), incidence type (cumulative incidence/1000 persons or incidence rate/1000 person-years), patient type (outpatients or in- and out-patients) and latitude to the base model-was also assessed. RESULTS: Sixty-one records from 59 studies were included in the analysis: 25, 20, 11 and 5 from Europe, North America, Asia and Oceania, respectively. There was variation in study methodology and outcomes. Heterogeneity of incidence rates was greatest among studies conducted in Asia. Meta-analysis showed that incidence increased with age, was lower in males compared to females, tended to be lower in Europe and North America compared to Asia and Oceania and increased with year of study data. The data-driven meta-regression model included continent, year of study data, gender, age and an age × gender interaction term. The difference in incidence between males and females was greater in younger ages (e.g., 50-59) compared to older age groups (e.g., 80+). None of the additional covariates contributed significantly to the model. CONCLUSION: Incidence rates were shown to vary by age, gender, continent and year of study data.

The intent of students to vaccinate is influenced by cultural factors, peer network, and knowledge about vaccines.

Young adults are the future vaccine decision-makers as parents or health-care professionals. To understand their attitudes and behaviors toward vaccination, we conducted a cross-sectional survey of 2079 students attending the University of Antwerp, Belgium and the University of Pisa, Italy. Principal component analysis was used to investigate associations between survey responses and the intent to vaccinate. Vaccination knowledge, attitudes, and behaviors among university students in Italy and Belgium were high. However, only one-half of respondents displayed an intent to vaccinate. High levels of knowledge, positive attitudes, and confidence in vaccines were positively associated with age, higher level of study, being a medical student, a recent vaccination experience, and not knowing trusted persons who did not believe in vaccines. Country of origin was highly correlated with the survey responses and was clustered with lifestyle, family, and data source variables, suggesting a strong modifying effect of culture and family attitudes on how vaccines are perceived in this age-group. Recent meningococcal vaccination campaigns and public discussions around mandatory vaccination in Italy may have influenced these results. We show that the intent to vaccinate was correlated with two main clusters of variables linked to culture (country, family, lifestyle), and to scholarship (knowledge, attitudes, data source) that together influence the behavior of students with respect to vaccination. Our study reinforces previous findings that knowledge about vaccines is key to shaping attitudes and behaviors, but also shows that cultural and lifestyle factors are another platform that could be leveraged in promoting vaccination among young people.

Association Between Hemagglutination Inhibition Antibody Titers and Protection Against Reverse-Transcription Polymerase Chain Reaction-Confirmed Influenza Illness in Children 6-35 Months of Age: Statistical Evaluation of a Correlate of Protection.

BACKGROUND: Data from a randomized controlled efficacy trial of an inactivated quadrivalent influenza vaccine in children 6-35 months of age were used to determine whether hemagglutination inhibition (HI) antibody titer against A/H1N1 and A/H3N2 is a statistical correlate of protection (CoP) for the risk of reverse-transcription polymerase chain reaction (RT-PCR)-confirmed influenza associated with the corresponding strain. METHODS: The Prentice criteria were used to statistically validate strain-specific HI antibody titer as a CoP. The probability of protection was identified using the Dunning model corresponding to a prespecified probability of protection at an individual level. The group-level protective threshold was identified using the Siber approach, leading to unbiased predicted vaccine efficacy (VE). A case-cohort subsample was used for this exploratory analysis. RESULTS: Prentice criteria confirmed that HI titer is a statistical CoP for RT-PCR-confirmed influenza. The Dunning model predicted a probability of protection of 49.7% against A/H1N1 influenza and 54.7% against A/H3N2 influenza at an HI antibody titer of 1:40 for the corresponding strain. Higher titers of 1:320 were associated with >80% probability of protection. The Siber method predicted VE of 61.0% at a threshold of 1:80 for A/H1N1 and 46.6% at 1:113 for A/H3N2. CONCLUSIONS: The study validated HI antibody titer as a statistical CoP, by demonstrating that HI titer is correlated with clinical protection against RT-PCR-confirmed influenza associated with the corresponding influenza strain and is predictive of VE in children 6-35 months of age. CLINICAL TRIALS REGISTRATION: NCT01439360.

Robust age at onset linkage analysis in nuclear families.

OBJECTIVE: Standard methods for linkage analysis ignore the phenotype of the parents when they are not genotyped. However, this information can be useful for gene mapping. In this paper we propose methods for age at onset genetic linkage analysis in sibling pairs, taking into account parental age at onset. METHODS: Two new score statistics are derived, one from an additive gamma frailty model and one from a log-normal frailty model. The score statistics are classical non-parametric linkage (NPL) statistics weighted by a function of the age at onset of the four family members. The weight depends on information from registries (age-specific incidences) and family studies (sib-sib and father-mother correlation). RESULTS: In order to investigate how age at onset of sibs and their parents affect the information for linkage analysis the weight functions were studied for rare and common disease models, realistic models for breast cancer and human lifespan. We studied the performance of the weighted NPL methods by simulations. As illustration, the score statistics were applied to the GAW12 data. The results show that it is useful to include parental age at onset information in genetic linkage analysis.