Reducing selection bias in case-control studies from rare disease registries

Background

Cockayne syndrome is a rare autosomal recessive neurodegenerative disease characterized by low-to-normal birth weight; growth failure; brain dysmyelination with calcium deposits, cutaneous photosensitivity; pigmentary retinopathy, cataract, and sensorineural hearing loss. To the best of our knowledge, cholestatic liver disease was not previously reported in these patients.

Aim

To highlight the presence of cholestasis and liver dysfunction in this group of patients and to suggest modified criteria for clinical diagnosis.

Methods

The study included nine patients with Cockayne from four different families (five males and four females) in which Cockayne was suspected clinically. In all patients chromosomal breakage studies revealed mild (45%) to moderate (60%) increase in frequency of chromatid and chromosome gaps and breaks versus 25% in normal controls. Diagnosis was confirmed by DNA repair assay.

Results

During routine follow up of these patients, seven of them had evident liver affection ranging from mild elevation in liver enzymes to cholestatic liver disease and liver cell failure. The attacks were recurrent in two patients and were sometimes preceded by infection. The attack may lead to deterioration of neurological and/or liver condition. It may end in liver cell failure that either recovers completely or may lead to death.

Conclusions

liver disease could be considered common in Egyptian patients with Cockayne with the cholestatic form being the most evident. The syndrome should be included in the list of causes of cholestatic liver disease. Chromosomal breakage study and positive family history should be included as major criteria for clinical diagnosis of Cockayne especially in a population like ours where consanguineous marriage is very high and molecular testing and UV sensitivity tests are considered unaffordable.     

Hormonal and reproductive risk factors of papillary thyroid cancer: A population-based case-control study in France

The three times higher incidence of thyroid cancer in women compared to men points to a role of female sex hormones in its etiology. However the effects of these factors are poorly understood. We analyzed the association between thyroid cancer and hormonal and reproductive factors among women enrolled in CATHY, a population-based case-control study conducted in France. The study included 430 cases of papillary thyroid cancer and 505 controls frequency-matched on age and area of residence. The odds ratios for thyroid cancer increased with age at menarche (p trend 0.05). Postmenopausal women were at increased risk, as compared to premenopausal women, particularly if menopause followed an ovariectomy, and for women with age at menopause < 55 years. In addition, use of oral contraceptives and menopausal hormone therapy reduced the association with thyroid cancer by about one third, and breastfeeding by 27%. Overall, these findings provide evidence that the risk of thyroid cancer increases with later age at menarche and after menopause, and decreases with use of oral contraceptives and menopausal hormone therapy. These findings confirm an implication of hormonal factors in papillary thyroid cancer risk, whose mechanisms need to be elucidated.     

Cancer incidence in Nigeria: A report from population-based cancer registries

Introduction: Cancer has become a major source of morbidity and mortality globally. Despite the threat that cancer poses to public health in sub-Saharan Africa (SSA), few countries in this region have data on cancer incidence. In this paper, we present estimates of cancer incidence in Nigeria based on data from 2 population-based cancer registries (PBCR) that are part of the Nigerian national cancer registry program. Materials and methods: We analyzed data from 2 population based cancer registries in Nigeria, the Ibadan Population Based Cancer Registry (IBCR) and the Abuja Population Based Cancer Registry (ABCR) covering a 2 year period 2009-2010. Data are reported by registry, gender and in age groups. We present data on the age specific incidence rates of all invasive cancers and report age standardized rates of the most common cancers stratified by gender in both registries. Results: The age standardized incidence rate for all invasive cancers from the IBCR was 66.4 per 100000 men and 130.6 per 100000 women. In ABCR it was 58.3 per 100000 for men and 138.6 per 100000 for women. A total of 3393 cancer cases were reported by the IBCR. Of these cases, 34% (1155) were seen among males and 66% (2238) in females. In Abuja over the same period, 1128 invasive cancers were reported. 33.6% (389) of these cases were in males and 66.4% (768) in females. Mean age of diagnosis of all cancers in men for Ibadan and Abuja were 51.1 and 49.9 years respectively. For women, mean age of diagnosis of all cancers in Ibadan and Abuja were 49.1 and 45.4 respectively. Breast and cervical cancer were the commonest cancers among women and prostate cancer the most common among men. Breast cancer age standardized incidence rate (ASR) at the IBCR was 52.0 per 100000 in IBCR and 64.6 per 100000 in ABCR. Cervical cancer ASR at the IBCR was 36.0 per 100000 and 30.3 per 100000 at the ABCR. The observed differences in incidence rates of breast, cervical and prostate cancer between Ibadan and Abuja, were not statistically significant. Conclusion: Cancer incidence data from two population based cancer registries in Nigeria suggests substantial increase in incidence of breast cancer in recent times. This paper highlights the need for high quality regional cancer registries in Nigeria and other SSA countries.     

Staging practices and breast cancer stage among population-based registries in the MENA region

BackgroundAvailability of stage information by population-based cancer registries (PBCR) remains scarce for diverse reasons. Nevertheless, stage is critical cancer control information particularly for cancers amenable to early detection. In the framework of the Global Initiative for Cancer Registry Development (GICR), we present the status of stage data collection and dissemination among registries in the Middle East and Northern Africa (MENA) region as well as the stage distribution of breast cancer patients.MethodsA web-based survey exploring staging practices and breast cancer stage was developed and sent to 30 PBCR in 18 countries of the MENA region.ResultsAmong 23 respondent PBCR, 21 collected stage data, the majority (80%) for all cancers. Fourteen registries used a single classification (9 TNM and 5 SEER), 7 used both staging systems in parallel. Out of 12,888 breast cancer patients (seven registries) 27.7% had unknown TNM stage (11.1% in Oman, 46% in Annaba). When considering only cases with known stage, 65.3% were early cancers (TNM I+II), ranging from 57.9% in Oman to 83.3% in Batna (Algeria), and 9.9% were stage IV cancers. Among the nine registries providing SEER Summary stage for breast cancer cases, stage was unknown in 19% of the cases, (0 in Bahrain, 39% in Kuwait). Stage data were largely absent from the published registry reports.ConclusionDespite wide stage data collection by cancer registries, missing information and low dissemination clearly limit informing efforts on early detection. The use of two classification systems in parallel implies additional workload and might undermine completeness. The favourable results of early cancer (TNM I+II) in two thirds of breast cancer patients needs to be interpreted with caution and followed up in time. Although efforts to improve quality of stage data are needed, our findings are particularly relevant to the WHO Global Breast Cancer Initiative.     

Effect of Pap-smear and sociodemographic factors on cervical cancer risk in Estonia: A population-based case-control study

BackgroundLike many Eastern-European countries, Estonia struggles with ineffective cervical cancer (CC) screening. Despite a long-term organised screening programme and high overall Pap-smear coverage, CC incidence and mortality remain very high. The aim of the study was to examine the reasons for high CC incidence in Estonia by analysing the effect of Pap-smears and sociodemographic factors on CC risk.MethodsIn this population-based case-control study, women aged ≥ 25 years with an in situ/invasive CC diagnosed in Estonia in 2011–2017 were defined as cases. Using a density sampling scheme, controls were randomly selected from general population. To estimate CC risk associated with having no Pap-smears during seven years before diagnosis (cases) or index date (controls), place of residence, interruption in health insurance, and several sociodemographic factors, multivariate logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI). Individual-level data from three population-based registries were used.ResultsAmong 1439 cases and 4317 controls, proportion of women with no Pap-smears was 53% and 35%, respectively. Women with no Pap-smears were at higher risk for CC (OR=2.35; 95% CI: 1.85–2.98). CC risk was increased among women who were younger, living in more remote regions, lower-educated, or divorced/widowed. Interruption in health insurance was associated with a 23% risk increase. Regional differences in CC risk were observed among screened women.ConclusionTo reduce the risk of CC in Estonia, efforts are necessary to increase screening coverage among high-risk women and ensure the quality of CC screening programme. Screening approaches and communication should be tailored to the needs of different population groups. Further studies are warranted to identify the reasons for regional differences in CC risk.     

Effects of cluster sampling on epidemiologic analysis in population-based case-control studies

We consider population-based case-control designs in which controls are selected by one of three cluster sampling plans from the entire population at risk. The effects of cluster sampling on classical epidemiologic procedures are investigated, and appropriately modified procedures are developed. In particular, modified procedures for testing the homogeneity of odds ratios across strata, and for estimating and testing a common odds ratio are presented. Simulations that use the data from the 1970 Health Interview Survey as a population suggest that classical procedures may be fairly robust in the presence of cluster sampling. A more extreme example based on a mixed multinomial model clearly demonstrates that the classical Mantel-Haenszel (1959, Journal of the National Cancer Institute 22, 719-748) and Woolf-Haldane tests of no exposure effect may have sizes exceeding nominal levels and confidence intervals with less than nominal coverage under an alternative hypothesis. Classical estimates of odds ratios may also be biased with non-self-weighting cluster samples. The modified procedures we propose remedy these defects.     

Abstracting stage in population-based cancer registries: The example of oral cavity and oropharynx cancers

Population-based cancer registries (PBCRs) are instruments to provide cancer incidence to promote cancer control and etiological research. A setting of mandatory (standard) variables is routinely collected for patient and tumor. One recommended variable is tumor stage, which supplies information on disease status and is an essential prognostic factor. However, it is not considered as necessary information to be collected by the PBCR. There are studies showing the value of stage as a prognostic variable to evaluate survival, socio-economic status, race and ethnics differences. Our aim is to analyze the feasibility of PBCRs in abstracting TNM for oral cavity and oropharynx. These topographies were selected due to the clinical accessibility of stage tumors by visual inspection and palpation. About 23% of the PBCRs who contributed to CI5-IX indicated their collection of TNM stage for all cancer sites. We analyzed 23,935 cases of oral cavity (OCC) and oropharynx cancer (OPC) from 13 PBCRs. Complete TNM stage for OCC was 52.7% for males and 47.6% for females; for OPC, it was 56% in both genders. Incomplete stage on OCC and OPC ranged from 22 to 25%. Missing was about 18–27% (most common in oral cavity). Missing stage was significantly higher in males for OCC aged ≥70 years, OR 1,64 (1.39–1.94). Our results demonstrate that OPC tend to have more stage, when compared with OCC. Even if it can be diagnosed by visual inspection, these results highlight the fact that information on stage can be a reliable indicator of access to healthcare and diagnosis awareness. Our results demonstrate that is feasible for PBCR to collect stage, although improving completeness of this information needs further technical training and international recommendation to adopt TNM stage as a standard variable for the PBCRs.     

Association between CASP3 polymorphisms and overall cancer risk: A meta-analysis of case-control studies

Several studies inspected the relationship between caspase-3 (CASP3) polymorphisms and the risk of several human cancers, but the findings remain controversial. We conducted a meta-analysis aiming to inspect the association between CASP3 rs1049216 T>C, rs12108497 C>T, rs4647603 G>A, rs4647602 C>A, rs6948 T>G, rs2705897 A>C, and rs113420705 G>A polymorphisms and cancer risk. Eligible studies were recognized by searching the Web of Science, PubMed, Scopus, and Google Scholar databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to quantitatively evaluate the association between each polymorphism of CASP3 and cancer risk. The rs4647603 variant significantly increased the risk of cancer in an overdominant (OR, 1.44; 95% CI, 1.03-2.01; P = 0.03; AG vs AA+GG) inheritance model. Regarding the rs4647602 variant, the findings revealed that this variant was associated with protection against cancer in homozygous codominant (OR, 0.67; 95% CI, 0.56-0.80; P < 0.00001; AA vs CC), dominant (OR, 0.84; 95% CI, 0.73-0.96; P = 0.009; AC+AA vs CC), recessive (OR, 0.70; 95% CI, 0.61-0.79; P < 0.00001; AA vs AC+CC), and allele (OR, 0.81; 95% CI, 0.75-0.88; P = 0.00001; A vs C) models. The findings suggested that the rs2705897 variant significantly decreased the risk of cancer in heterozygous codominant (OR, 0.80; 95% CI, 0.67-0.94; P = 0.009; AC vs AA), dominant (OR, 0.81; 95% CI, 0.69-0.95; P = 0.009; AC+CC vs AA), overdominant (OR, 0.80; 95% CI, 0.68-0.95; P = 0.01; AC vs CC+AA), and allele (OR, 0.85; 95% CI, 0.74-0.97; P = 0.02; C vs A) models. The results did not support an association between CASP3 rs1049216 and rs6948 polymorphisms and cancer risk. In summary, the findings of this meta-analysis support an association between CASP3 polymorphisms and cancer risk. Larger and well-designed studies are desired to evaluate these associations in detail.     

Main dietary compounds and pancreatic cancer risk. The quantitative analysis of case-control and cohort studies

Objective: Estimation of the role of main dietary compounds in the risk of developing pancreatic cancer. Research methods and procedures: Literature published till 2010 was reviewed and selected for further analysis. The used terms were: red meat, minced meat, ham, bacon, sausages, white meat, poultry, vegetables, fish, eggs, fruits, lifestyle, diet, pancreatic cancer and pancreatic neoplasm. The collected data were meta-analysed with calculation of combined relative risk and 95% confidence interval as well as studies heterogeneity. Results: A meta-analysis of 11 case–control studies indicates that red meat ingestion elevates pancreatic cancer risk by 48% (95% CI = 1.25–1.76). The vegetables and fruit reduce the risk by 38% (95% CI = 0.54–0.73) and 29% (95% CI = 0.59–0.84), respectively. The pooled analyses of 10 cohort studies do not show significant relations between main dietary compound ingestion and pancreatic cancer risk. Conclusion: The red meat intake is associated with elevated risk of pancreatic cancer in contrast to vegetables and fruit ingestion. The ingestion of red meat, vegetables and fruit in cohort studies was not influenced on pancreatic cancer risk. The role of fish, poultry and eggs was not significant in both case–control and cohort studies, thus further studies were needed.     

Regional differences in patient age and prostate cancer characteristics and rates of treatment modalities in favorable and unfavorable intermediate risk prostate cancer across United States SEER registries

BackgroundIntermediate risk (IR) prostate cancer (PCa) is a highly heterogeneous entity and can be distinguished into favorable and unfavorable IR PCa according to biopsy, PSA and cT-stage characteristics. These differences may translate into differences in treatment type.MethodsWe tested for differences in PCa tumor characteristics and differences in active treatment rates (radical prostatectomy [RP], external beam radiotherapy [EBRT]) according to Surveillance, Epidemiology and End Results (SEER) registry (2010−2015) in favorable and unfavorable IR PCa. Data were stratified according to individual SEER registries. Further analyses additionally adjusted for PCa baseline characteristics (PSA, cT stage, biopsy Gleason group grading [GGG], percentage of positive biopsy cores).ResultsTabulations according to SEER registries showed that, in favorable IR vs. unfavorable IR, the rates of RP and EBRT respectively ranged from 30.0 to 54.3% vs. 30.3–55.5 % and 8.3–44.7 % vs. 11.5–45.5 %. Differences in age and baseline PCa tumor characteristics also existed in both favorable and unfavorable IR across SEER registries. After adjustment for those baseline patient and PCa characteristics (PSA, cT stage, GGG, percentage of positive biopsy cores), RP and EBRT rates exhibited virtually no residual differences across individual SEER registries, in both favorable (36.0–41.0 % and 26.8–28.1 %) and unfavorable IR PCa (39.2−42.0% and 31.1–33.5 %).ConclusionImportant differences may be identified in treatment rates within the examined 18 SEER registries in favorable and in unfavorable IR PCa. However, the observed differences are virtually entirely explained by differences in baseline PCa characteristics.     

Occupational exposure to petroleum-based and oxygenated solvents and oral and oropharyngeal cancer risk in men: A population-based case-control study in France

ObjectiveTo examine the association between occupational exposure to petroleum-based and oxygenated solvents and the risk of oral and oropharyngeal cancer.MethodsThe ICARE study is a large population-based case-control study conducted in France between 2001 and 2007. This present analysis was restricted to men and included 350 and 543 cases of squamous cell-carcinoma of the oral cavity and oropharynx, respectively, and 2780 controls. Lifetime tobacco, alcohol consumption and complete occupational history were assessed through detailed questionnaires. Job-exposure matrices allowed us to assess occupational exposure to five petroleum-based solvents (white spirits; diesel/fuel oils/kerosene; gasoline; benzene; special petroleum products) and five oxygenated solvents (diethyl ether; tetrahydrofuran; ketones and esters; alcohols; ethylene glycol). Odds-ratios (ORs), adjusted for age, smoking, alcohol consumption and socioeconomic status, and 95% confidence intervals (CI) were estimated using unconditional logistic models.ResultsAssociations between oral cancer risk and exposure to white spirits and diesel/fuel oils/kerosene were suggested, but there was no exposure-response trend. Concerning exposure to oxygenated solvents, participants with the highest levels of cumulative exposure to diethyl ether had a significant excess risk of oropharyngeal cancer (OR = 7.78, 95%CI 1.42 to 42.59; p for trend = 0.04). Ever exposure to tetrahydrofuran was associated with a borderline significant increased risk of oral cancer (OR = 1.87, 95%CI 0.97 to 3.61), but no exposure-response trend was observed. Additional adjustments for exposure to other solvents did not substantially change the results.ConclusionOur results do not provide evidence for a major role of petroleum-based and oxygenated solvents in the occurrence of oral and oropharyngeal cancers in men.     

Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk

To characterize cancer risk in heterozygous p53 mutation carriers, we analyzed cancer incidence in 56 germline p53 mutation carriers and 3,201 noncarriers from 107 kindreds ascertained through patients with childhood soft-tissue sarcoma who were treated at the University of Texas M. D. Anderson Cancer Center. We systematically followed members in these kindreds for cancer incidence for >20 years and evaluated their p53 gene status. We found seven kindreds with germline p53 mutations that include both missense and truncation mutation types. Kaplan-Meier analysis showed similar cancer risks between 21 missense and 35 truncation p53 mutation carriers (log-rank chi(2)=0.04; P=.84). We found a significantly higher cancer risk in female carriers than in male carriers (log-rank chi(2)=12.1; P<.001), a difference not explained by an excess of sex-specific cancer. The calculated standardized incidence ratio (SIR) showed that mutation carriers had a risk for all types of cancer that was much higher than that for the general population (SIR = 41.1; 95% confidence interval [CI] 29.9-55.0) whereas noncarriers had a risk for all types of cancer that was similar to that in the general population (SIR = 0.9; 95% CI 0.8-1.0). The calculated SIRs showed a >100-fold higher risk of sarcoma, female breast cancer, and hematologic malignancies for the p53 mutation carriers and agreed with the findings of an earlier segregation analysis based on the same cohort. These results quantitatively illustrated the spectrum of cancer risk in germline p53 mutation carriers and will provide valuable reference for the evaluation and treatment of patients with cancer.