Fate of biomedical research protocols and publication bias in France: retrospective cohort study

Objectives To describe the fate of protocols approved by the French research ethics committees, a national system created by the French 1988 Huriet-Sérusclat Act; to assess publication bias at a national level.Design Retrospective cohort study.Setting Representative sample of 25/48 French research ethics committees in 1994.Protocols 649 research protocols approved by committees, with follow-up information.Main outcome measures Protocols'' initial characteristics (design, study size, investigator) abstracted from committees'' archives; follow-up information (rates of initiation, completion, and publication) obtained from mailed questionnaire to principal investigators.Results Completed questionnaires were available for 649/976 (69%) protocols. Of these, 581 (90%) studies were initiated, 501/581 (86%) were completed, and 190/501 (38%) were published. Studies with confirmatory results were more likely to be published as scientific papers than were studies with inconclusive results (adjusted odds ratio 4.59, 95% confidence interval 2.21 to 9.54). Moreover, studies with confirmatory results were published more quickly than studies with inconclusive results (hazard ratio 2.48, 1.36 to 4.55).Conclusion At a national level, too many research studies are not completed, and among those completed too many are not published. We suggest capitalising on research ethics committees to register and follow all authorised research on human participants on a systematic and prospective basis.     

Influence of variation in birth weight within normal range and within sibships on IQ at age 7 years: cohort study

ObjectiveTo examine the relation between birth weight and measured intelligence at age 7 years in children within the normal range of birth weight and in siblings.DesignCohort study of siblings of the same sex.Setting12 cities in the United States.Subjects3484 children of 1683 mothers in a birth cohort study during the years 1959 through 1966. The sample was restricted to children born at ⩾37 weeks gestation and with birth weights of 1500-3999 g.ResultsMean IQ increased monotonically with birth weight in both sexes across the range of birth weight in a linear regression analysis of one randomly selected sibling per family (n= 1683) with adjustment for maternal age, race, education, socioeconomic status, and birth order. Within same sex sibling pairs, differences in birth weight were directly associated with differences in IQ in boys (812 pairs, predicted IQ difference per 100 g change in birth weight =0.50, 95% confidence interval 0.28 to 0.71) but not girls (871 pairs, 0.10, −0.09 to 0.30). The effect in boys remained after differences in birth order, maternal smoking, and head circumference were adjusted for and in an analysis restricted to children with birth weight ⩾ 2500 g.ConclusionThe increase in childhood IQ with birth weight continues well into the normal birth weight range. For boys this relation holds within same sex sibships and therefore cannot be explained by confounding from family social environment.

What is already known on this topic

IQ at school age is linked to birth weight among low birthweight babiesSome evidence suggests the association might also apply to children of normal birth weight

What this study adds

IQ at age 7 years is linearly related to birth weight among children of normal birth weightThe relation was not due to confounding by maternal or socioeconomic factorsIQ is also associated with differences in birth weight between boy sibling pairs but not girls     

Publication bias: evidence of delayed publication in a cohort study of clinical research projects.

OBJECTIVES: To determine the extent to which publication is influenced by study outcome. DESIGN: A cohort of studies submitted to a hospital ethics committee over 10 years were examined retrospectively by reviewing the protocols and by questionnaire. The primary method of analysis was Cox''s proportional hazards model. SETTING: University hospital, Sydney, Australia. STUDIES: 748 eligible studies submitted to Royal Prince Alfred Hospital Ethics Committee between 1979 and 1988. MAIN OUTCOME MEASURES: Time to publication. RESULTS: Response to the questionnaire was received for 520 (70%) of the eligible studies. Of the 218 studies analysed with tests of significance, those with positive results (P < 0.05) were much more likely to be published than those with negative results (P > or = 0.10) (hazard ratio 2.32 (95% confidence interval 1.47 to 3.66), P = 0.0003), with a significantly shorter time to publication (median 4.8 v 8.0 years). This finding was even stronger for the group of 130 clinical trials (hazard ratio 3.13 (1.76 to 5.58). P = 0.0001), with median times to publication of 4.7 and 8.0 years respectively. These results were not materially changed after adjusting for other significant predictors of publication. Studies with indefinite conclusions (0.05 < or = P < 0.10) tended to have an even lower publication rate and longer time to publication than studies with negative results (hazard ratio 0.39 (0.13 to 1.12), P = 0.08). For the 103 studies in which outcome was rated qualitatively, there was no clear cut evidence of publication bias, although the number of studies in this group was not large. CONCLUSIONS: This study confirms the evidence of publication bias found in other studies and identifies delay in publication as an additional important factor. The study results support the need for prospective registration of trials to avoid publication bias and also support restricting the selection of trials to those started before a common date in undertaking systematic reviews.     

The utility of repeated presence data as a surrogate for counts: a case study using butterflies

Abundance data are widely used to monitor long-term population trends for management and conservation of species of interest. Programs that collect count data are often prohibitively expensive and time intensive, limiting the number of species that can be simultaneously monitored. Presence data, on the other hand, can often be collected in less time and for multiple species simultaneously. We investigate the relationship of counts to presence using 49 butterfly species across 4 sites over 9 years, and then compare trends produced from each index. We also employed simulated datasets to test the effect of reduced sampling on the relationship of counts to presence data and to investigate changes in each index’s power to reveal population trends. Presence and counts were highly correlated for most species tested, and population trends based on each index were concordant for most species. The effect of reduced sampling was species-specific, but on a whole, sensitivity of both indices to detect population trends was reduced. Common and rare species, as well as those with a range of life-history and behavioral traits performed equally well. The relationship between presence and count data may break down in cases of very abundant and widespread species with extended flight seasons. Our results suggest that when used cautiously, presence data has the potential to be used as a surrogate for counts. Collection of presence data may be useful for multi-species monitoring or to reduce the duration of monitoring visits without fully sacrificing the ability to infer population trends.     

Association between metabolic syndrome and participation in colorectal cancer screening in Japan: A retrospective cohort analysis using LIFE study data

BackgroundPeople with metabolic syndrome have an elevated risk of developing colorectal cancer (CRC), and are recommended to undergo cancer screening. This study examined the association between metabolic syndrome and CRC screening participation in Japan.MethodsThis retrospective cohort study was conducted using insurance claims data, health checkup data, and cancer screening data from a Japanese city. The study population comprised persons aged 40–74 years who had undergone health checkups between fiscal years (FY) 2016 and 2019. The exposure was metabolic syndrome risk (high risk, moderate risk, and no risk) as determined during health checkups. The outcome was CRC screening participation. Logistic regression analyses were performed to examine the associations between metabolic syndrome risk and CRC screening participation.ResultsWe analyzed 20,558 people in the FY2016 cohort, 19,065 people in the FY2017 cohort, 17,496 people in the FY2018 cohort, and 15,647 people in the FY2019 cohort. The odds of CRC screening participation were significantly lower in the moderate-risk group (P < 0.05) in all FYs except FY2019 and the high-risk group (P < 0.001) in all FYs when compared with the no-risk group. When analyzed according to age group, older persons aged 65–74 years generally had significantly lower odds of CRC screening participation than persons aged 40–49 years across all metabolic syndrome risk groups.ConclusionThis is the first study from Japan to show that people with metabolic syndrome, especially older persons aged 65–74 years, are less likely to undergo CRC screening than people without metabolic syndrome. These findings indicate a need to develop and implement age-specific measures to increase cancer screening uptake among persons with metabolic syndrome.     

Reproduction in Brahman cows calving for the first time at two or three years of age

A comparison of the subsequent reproduction of heifers that calved for the first time at 2 vs. 3 yr of age was conducted on a purebred Brahman herd from 1971 to 1978 in central Florida. Pregnancy rate, birth rate and weaning rate were obtained on 1,612 animals. Sire of the cow had a significant effect on all three reproduction traits, indicating possible genetic differences in these important traits. Age at first calving (either 2 or 3 yr) had no significant effect on overall reproduction rates; however, subsequent pregnancy and weaning rate was 4% higher in females calving first at 2 yr of age. Thirty-eight percent of the females that became pregnant at 15 to 17 mo of age, weighed 650 to 700 lbs. These heifers had been born early in the previous calving season. It is suggested that Brahmans can be selected to calve at 2 yr of age if good nutrition and management are provided.     

School screening for scoliosis: cohort study of clinical course.

A visual examination of 1764 Oxford schoolchildren for scoliosis was followed by low-dose radiography of the spine in those who showed evidence of asymmetric body topography; radiography was repeated a year later to assess progression. Forty-four children had curves of 10 degrees or more. Two had a congenital abnormality and the remaining 42 were classified according to the type of curve: sacral tilt (compensatory), spinal (idiopathic), or combined (sacral tilt and spinal). Progression occurred in 6 (14%) children, none of whom had only a sacral tilt. These results suggest that only by measuring sacral tilt can benign compensatory curves be differentiated from true idiopathic scoliosis.     

Trial of brief intermittent neuroleptic prophylaxis for selected schizophrenic outpatients: clinical and social outcome at two years.

OBJECTIVE--To evaluate a novel approach to the prophylaxis of schizophrenic relapse characterised by administration of brief courses of neuroleptic for the earliest non-psychotic signs of relapse (prodromal symptoms). DESIGN--Two year follow up of subjects randomised, double blind, to receive either active (control group) or placebo (intermittent group) depot neuroleptic medication. Both groups received brief courses of oral neuroleptic when prodromal symptoms or relapse occurred. SETTING--Psychiatric outpatient department, Charing Cross Hospital, London. SUBJECTS--54 Stable patients in remission who met the American Psychiatric Association''s DSM-III criteria for schizophrenia on the basis of case notes. MAIN OUTCOME MEASURES--Survival without relapse, survival without hospitalisation, point prevalence of extrapyramidal side effects and tardive dyskinesia, structured assessment of social functioning (social adjustment scale II), and frequency of prodromal symptoms. RESULTS--Of 19 relapses recorded over two years, 10 (53%) were preceded by non-psychotic prodromal signs. Survival rates for both relapse and hospitalisation were worse with intermittent treatment than continuous treatment over the two year follow up: 92% of controls and only 54% of patients given intermittent treatment survived the two year period without hospitalisation. Prolonged or frequent relapses as well as episodes of prodromal symptoms were more frequent with intermittent treatment. Lower scores for extrapyramidal side effects were recorded in the intermittent treatment group, but periodic assessments of social functioning failed to show any social advantages from this. CONCLUSION--The findings are at variance with a previous report of one year follow up in this cohort and attest to the superiority of continuous depot neuroleptic prophylaxis in preventing both psychotic and neurotic or dysphoric morbidity in schizophrenia.     

Artificial insemination with frozen semen in dogs: a retrospective study of 10 years using a non-surgical approach

From 1994 to 2003, a total of 526 bitches of 99 different breeds were artificially inseminated in 685 estrus cycles with domestic (n = 353) or imported (n = 332) frozen-thawed semen from 368 males. The overall whelping rate was 73.1% and mean (+/- S.E.M.) litter size 5.7 +/- 0.1 pups. The whelping rate was higher after intrauterine insemination (75.0%; n = 665) than after intravaginal insemination (10.0%, n = 20; P < 0.05). Insemination at the optimal time resulted in a higher whelping rate (78%, n = 559; P < 0.01) and larger litter size (5.8 +/- 0.2; P < 0.05) than inseminations performed late or too late (55.7% and 4.5 +/- 0.5, n = 61). Two inseminations (n = 384) yielded a higher whelping rate (P < 0.05) and mean litter size (P < 0.01) than one insemination (n = 241), 78.1% and 6.0 +/- 0.2 and 70.5% and 5.1 +/- 0.2, respectively. For inseminations performed at the optimal time, however, the whelping rate was not significantly different for bitches inseminated twice (79.3%, n = 358) versus once (76.8%, n = 168), but the litter size was larger (6.0 +/- 0.2 and 5.3 +/- 0.3). Semen classified as of poor quality (progressive motility < 50% or percentage abnormal sperm > 20%) resulted in a lower whelping rate (P < 0.01) than semen classified as of good quality (progressive motility > or = 50% and percentage abnormal sperm < or = 20%), 61 and 77%, respectively. Small breeds (n = 50) had a smaller litter size (3.9 +/- 0.3; P < 0.01) than larger breeds (medium [5.7 +/- 0.3, n = 94], large [5.9 +/- 0.2, n = 295] or giant breeds [6.1 +/- 0.5, n = 62] [P < 0.01]). Bitches older than 6 years had a lower whelping rate (68.2%) than younger ones (77.0%; P < 0.05). The duration of pregnancy was longer (P < 0.01) for bitches with a litter size of < 3 pups (61.7 +/- 0. 4 days, n = 30) than for bitches with larger litters (60.5 +/- 0.1 days, n = 177). These results show the potential of transcervical intrauterine insemination for routine artificial insemination in dogs. The results with frozen semen inseminations were optimised by inseminating bitches < or = 6 years old 2 and 3 days after ovulation with semen of good quality from males < or = 8 years old.     

Improved long-term results of intensity-modulated radiotherapy for a non-endemic European nasopharyngeal carcinoma cohort: single-center retrospective study

PurposeReport our matured outcomes of European nasopharyngeal carcinoma (NPC) treatment from a non-endemic region in the IMRT era.MethodsWe reviewed 109 consecutive patients with biopsy proven NPC treated between 2009 and 2013. All received IMRT as per RTOG 0615. Toxicity was scored accordingly to CTCAE 4.03. Platinum-based chemotherapy was delivered following the Intergroup 0099.ResultsMedian age of 53 years; 97% Caucasian; 74% male; 72% WHO grade III; 43% T1; 14% T2; 18% T3, 25% T4; 17% N0; 17% N1; 39% N2; 27% N3. Compliance to adjuvant chemotherapy was 88%. With a median follow up of 56 months, the 4-year local control was 90.2% (88.6% for T1; 100% for T2; 85% for T3; and 91.7% for T4), the 4-year distant metastases-free survival was 86% and an overall survival rate was 77%. Local control and survival were better in G3 (p < 0.001 and p = 0.032, respectively). Xerostomia was the most frequent late toxicity in 55% (n = 60). Hypothyroidism requiring hormonal reposition occurred in 15.5% (n = 17). From the 36 deaths, 20 were due to distant metastases, 3 grade 5 toxicity, 2 from local progression, 5 non-cancer deaths and unknown cause in the remaining 6. On multivariable analysis, age (p = 0.017), local recurrence and distant metastases were associated with death (p < 0.001, both).ConclusionOur matured data from the IMRT era showed a major improvement from our 3D cohort series reaching excellent local and regional control, even in T4. Local recurrences, despite few, and distant metastases were correlated with the risk of death.     

Efficacy and safety of autologous stem cell transplantation for decompensated liver cirrhosis: A retrospective cohort study

AIM To evaluate the long-term efficacy and safety of autologous stem cell transplantation(SCT) for decompensated liver cirrhosis.METHODS Consecutive patients with decompensated liver cirrhosis were included and assigned into the SCT group and non-transplantation(non-SCT) group according to whether they received SCT treatment. Patients werefollowed up for ten years. The long-term survival rate and incidence of hepatocellular carcinoma(HCC) were compared between groups.     

Estimated number of multiplets under 16 years using two sets of census data in Japan: 1990 and 1995.

Data for sets of multiples under 16 years of age were obtained from the population censuses of Japan in 1990 and 1995. These numbered 147,188 twin pairs, 1410 sets of triplets, 59 sets of quadruplets, and 3 sets of quintuplets in 1990, with the corresponding numbers in 1995 being 141,354, 2,211, 136 and 12, respectively. The total number of sets of multiples was 148,660 in 1990 and 143,713 in 1995. Twinning, triplet, quadruplet and quintuplet rates were estimated for each age. Rates of monozygotic twins and triplets remained constant age by age up to 15 years, while the dizygotic twinning rate, and rates of di- and tri-zygotic triplets decreased over the same period. Quadruplet and quintuplet rates also decreased. The accuracy of estimating number of multiples from census data is discussed using data on vital statistics.     

Assessment of risk factors for postoperative cognitive dysfunction after coronary artery bypass surgery: a single-center retrospective cohort study

Aim: To find out risk factors for postoperative cognitive dysfunction (POCD) after coronary artery bypass grafting (CABG), and to provide basis for clinical prevention of POCD. A total of 88 patients who underwent CABG were surveyed with Telephone Questionnaire (TICS-M) for their cognitive impairment after 3, 7, 21, 90, 180 days post-surgery. The occurrence of POCD was diagnosed by Neuropsychological Battery which included Vocabular Learning Test (VLT), Wisconsin Card Sorting Test (WCST), Trail Making Test (TMT) and Symbol Digit Modalities Test (SDMT). The preoperative, intraoperative and postoperative risk factors were assessed by the χ² or t test. Multivariate analysis was used to study the correlation between the risk factors and the occurrence of POCD. Age, aortic plaque, carotid artery stenosis, cerebrovascular disease, anesthesia time, the rate of decline in intraoperative hemoglobin concentration (ΔHb) and systemic inflammatory response syndrome (SIRS) score on postoperative day 2 had statistically significant (P<0.05) influence on the occurrence of POCD. Aortic plaque, carotid artery stenosis, anesthesia time and SIRS score (odds ratio (OR) value > 1, P<0.05) are the risk factors for POCD. The incidence of day-21 and -180 POCD was approximately 26.1 and 22.7%, respectively.     

Maternal influenza immunization and reduced likelihood of prematurity and small for gestational age births: a retrospective cohort study

Background

Infections during pregnancy have the potential to adversely impact birth outcomes. We evaluated the association between receipt of inactivated influenza vaccine during pregnancy and prematurity and small for gestational age (SGA) births.

Methods and Findings

We conducted a cohort analysis of surveillance data from the Georgia (United States) Pregnancy Risk Assessment Monitoring System. Among 4,326 live births between 1 June 2004 and 30 September 2006, maternal influenza vaccine information was available for 4,168 (96.3%). The primary intervention evaluated in this study was receipt of influenza vaccine during any trimester of pregnancy. The main outcome measures were prematurity (gestational age at birth <37 wk) and SGA (birth weight <10th percentile for gestational age). Infants who were born during the putative influenza season (1 October–31 May) and whose mothers were vaccinated against influenza during pregnancy were less likely to be premature compared to infants of unvaccinated mothers born in the same period (adjusted odds ratio [OR] = 0.60; 95% CI, 0.38–0.94). The magnitude of association between maternal influenza vaccine receipt and reduced likelihood of prematurity increased during the period of at least local influenza activity (adjusted OR = 0.44; 95% CI, 0.26–0.73) and was greatest during the widespread influenza activity period (adjusted OR = 0.28; 95% CI, 0.11–0.74). Compared with newborns of unvaccinated women, newborns of vaccinated mothers had 69% lower odds of being SGA (adjusted OR = 0.31; 95% CI, 0.13–0.75) during the period of widespread influenza activity. The adjusted and unadjusted ORs were not significant for the pre-influenza activity period.

Conclusions

This study demonstrates an association between immunization with the inactivated influenza vaccine during pregnancy and reduced likelihood of prematurity during local, regional, and widespread influenza activity periods. However, no associations were found for the pre-influenza activity period. Moreover, during the period of widespread influenza activity there was an association between maternal receipt of influenza vaccine and reduced likelihood of SGA birth. Please see later in the article for the Editors'' Summary     

Rapid identification of bacteria and candida using pna-fish from blood and peritoneal fluid cultures: a retrospective clinical study

Background

Peptide nucleic acid fluorescent in situ hybridization (PNA-FISH) is a rapid and established method for identification of Candida sp., Gram positive, and Gram negative bacteria from positive blood cultures. This study reports clinical experience in the evaluation of 103 positive blood cultures and 17 positive peritoneal fluid cultures from 120 patients using PNA-FISH. Our study provides evidence as to potential pharmaceutical cost savings based on rapid pathogen identification, in addition to the novel application of PNA-FISH to peritoneal fluid specimens.

Methods

Identification accuracy and elapsed time to identification of Gram positives, Gram negatives, and Candida sp., isolated from blood and peritoneal fluid cultures were assessed using PNA-FISH (AdvanDx), as compared to standard culture methods. Patient charts were reviewed to extrapolate potential pharmaceutical cost savings due to adjustment of antimicrobial or antifungal therapy, based on identification by PNA-FISH.

Results

In blood cultures, time to identification by standard culture methods for bacteria and Candida sp., averaged 83.6 hours (95% CI 56.7 to 110.5). Identification by PNA-FISH averaged 11.2 hours (95% CI 4.8 to 17.6). Overall PNA-FISH identification accuracy was 98.8% (83/84, 95% CI 93.5% to 99.9%) as compared to culture. In peritoneal fluid, identification of bacteria by culture averaged 87.4 hours (95% CI ?92.4 to 267.1). Identification by PNA-FISH averaged 16.4 hours (95% CI ?57.3 to 90.0). Overall PNA-FISH identification accuracy was 100% (13/13, 95% CI 75.3% to 100%). For Candida sp., pharmaceutical cost savings based on PNA-FISH identification could be $377.74/day. For coagulase-negative staphylococcus (CoNS), discontinuation of vancomycin could result in savings of $20.00/day.

Conclusions

In this retrospective study, excellent accuracy of PNA-FISH in blood and peritoneal fluids with reduced time to identification was observed, as compared to conventional culture-based techniques. Species-level identification based on PNA-FISH could contribute to notable cost savings due to adjustments in empiric antimicrobial or antifungal therapy as appropriate to the pathogen identified.     

Development and validation of two nomograms for predicting overall survival and cancer-specific survival in gastric cancer patients with liver metastases: A retrospective cohort study from SEER database

BackgroundGastric cancer is heterogeneous and aggressive, especially with liver metastasis. This study aims to develop two nomograms to predict the overall survival (OS) and cancer-specific survival (CSS) of gastric cancer with liver metastasis (GCLM) patients.MethodsFrom January 2000 to December 2018, a total of 1936 GCLM patients were selected from the Surveillance, Epidemiology, and End Results Program (SEER) database. They were further divided into a training cohort and a validation cohort, with the OS and CSS serving as the study's endpoints. The correlation analyses were used to determine the relationship between the variables. The univariate and multivariate Cox analyses were used to confirm the independent prognostic factors. To discriminate and calibrate the nomogram, calibration curves and the area under the time-dependent receiver operating characteristic curve (time-dependent AUC) were used. DCA curves were used to examine the accuracy and clinical benefits. The clinical utility of the nomogram and the AJCC Stage System was compared using net reclassification improvement (NRI) and integrated differentiation improvement (IDI) (IDI). Finally, the nomogram and the AJCC Stage System risk stratifications were compared.ResultsThere was no collinearity among the variables that were screened. The results of multivariate Cox regression analysis showed that six variables (bone metastasis, lung metastasis, surgery, chemotherapy, grade, age) and five variables (lung metastasis, surgery, chemotherapy, grade, N stage) were identified to establish the nomogram for OS and CSS, respectively. The calibration curves, time-dependent AUC curves, and DCA revealed that both nomograms had pleasant predictive power. Furthermore, NRI and IDI confirmed that the nomogram outperformed the AJCC Stage System.ConclusionBoth nomograms had satisfactory accuracy and were validated to assist clinicians in evaluating the prognosis of GCLM patients.     

Benefits of plerixafor for mobilization of peripheral blood stem cells prior to autologous transplantation: a dual-center retrospective cohort study

Background aimsBefore autologous stem cell transplantation (ASCT), hematopoietic stem cells must be stimulated to move from the bone marrow to the peripheral blood for harvesting. Plerixafor, a C-X-C chemokine receptor type 4 antagonist, is used to increase stem cell harvests. However, the effects of plerixafor on post-ASCT outcomes remain unclear.MethodsIn a dual-center retrospective cohort study of 43 Japanese patients who received ASCT, the authors compared transplantation outcomes in patients who underwent stem cell mobilization with granulocyte colony-stimulating factor with (n = 25) or without (n = 18) plerixafor.ResultsThe number of days to neutrophil and platelet engraftment was significantly shorter with plerixafor than without plerixafor, as assessed by univariate (neutrophil, P = 0.004, platelet, P = 0.002), subgroup, propensity score matching and inverse probability weighting analyses. Although the cumulative incidence of fever was comparable with or without plerixafor (P = 0.31), that of sepsis was significantly lower with plerixafor than without (P < 0.01). Thus, the present data indicate that plerixafor leads to earlier neutrophil and platelet engraftment and a reduction of infectious risk.ConclusionsThe authors conclude that plerixafor may be safe to use and that it reduces the risk of infection in patients with a low CD34+ cell count the day before apheresis.     

Comparison of the linkage results of two phenotypic constructs from longitudinal data in the Framingham Heart Study: analyses on data measured at three time points and on the average of three measurements

Background

Family studies are often conducted in a cross-sectional manner without long-term follow-up data. The relative contribution of a gene to a specific trait could change over the lifetime. The Framingham Heart Study offers a unique opportunity to investigate potential gene × time interaction. We performed linkage analysis on the body mass index (BMI) measured in 1970, 1978, and 1986 for this project.

Results

We analyzed the data in two different ways: three genome-wide linkage analyses on each exam, and one genome-wide linkage analysis on the mean of the three measurements. Variance-component linkage analyses were performed by the SOLAR program. Genome-wide scans show consistent evidence of linkage of quantitative trait loci (QTLs) on chromosomes 3, 6, 9, and 16 in three measurements with a maximum multipoint LOD score > 2.2. However, only chromosome 9 has a LOD score = 2.14 when the mean values were analyzed. More interestingly, we found potential gene × environment interactions: increasing LOD scores with age on chromosomes 3, 9, and 16 and decreasing LOD scores on chromosome 6 in the three exams.

Conclusion

The results indicate two points: 1) it is possible that a gene (or genes) influencing BMI is (are) up- or down-regulated as people aged due to aging process or changes in lifestyle, environments, or genetic epistasis; 2) using mean values from longitudinal data may reduce the power to detect linkage and may have no power to detect gene × time, and/or gene × gene interactions.