General formulas of the estimated likelihood ratio Y/X in the diagnosis of paternity of a deceased putative father

Summary When the putative father is dead his probable genotype, essential for estimate of likelihood ratio in the diagnosis of paternity, should be deduced from his relatives. In the present paper are described the general method for such deduction of probable genotype and the derivation of the formula of likelihood ratio. 10⁴ examples of the diagnosis of paternity of deceased father are examined using a Monte Carlo method and the distributions of relative frequencies of log(Y/X) are calculated for the true father and non-father. These results indicate that the present method of estimation of Y/X from relatives is quite useful for the diagnosis of paternity of a deceased putative father.     

Die Berechnung der Vaterschaftswahrscheinlichkeit und der Vaterschaftsausschlußchance im HLA System auf Grund der Befunde des Kindes und des Präsumtivvaters ohne Einbeziehung der Mutter

Zusammenfassung Eine Methode zur Berechnung der Vaterschaftswahrscheinlichkeit im HLA System auf Grund der Befunde des Kindes und des Pr?sumtivvaters ohne Einbeziehung der Kindesmutter wird angegeben und die Anwendbarkeit der Formeln von Mayr und Pausch (Z. Immun.-Forsch.150, 447 (1975)) zur Bestimmung der Vaterschaftsausschlu?chance für solche F?lle demonstriert.

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Summary A method for the calculation of the probability of paternity for the HLA system using only the typing results from the child and the putative father, without taking into account the data of the mother, is presented. Furthermore, the usability of the formulas by Mayr and Pausch (Z. Immun.-Forsch.150, 447 (1975)) for the computation of the chance of paternity exclusion in such cases is demonstrated.

National Blood Group Reference Laboratory (WHO) und National Tissue Typing Reference Laboratory (Council of Europe)     

Biostatistical evaluation of blood group,HLA and DNA findings in Jeffreys' immigrant test-case using special kinship and DNA algorithms

Summary In the immigration case cited by Jeffreys et al. (1985), the biostatistical evaluation of blood group findings in 16 systems and of HLA-A,B findings for the mother and child, using a special kinship algorithm developed by Ihm and Hummel (1975), produced a probability of maternity of the Ghanaian-born putative mother of W = 6%; the probability of maternity for her sister was W = 94%. Using the DNA multilocus probes 33.15 and 33.6 and the bandsharing technique, the authors analysed band patterns from the putative mother and child as well as another 3 children of the same woman. It was concluded that the putative mother was the mother of all 4 children. An evaluation of the band patterns using the multi-di-allelism model and the kinship algorithm in accordance with the Essen-Möller principle produced: W = 99.99999999999999991%, or, if the ----- constellations were not considered, W = 99.99998%.     

Paternity evaluation in cases lacking a mother and nondetectable alleles

In parentage testing the formulae for computing paternity index and exclusion probability generally ignores the presence of nondetectable alleles at the loci tested. In contrast, it is now known that even when paternity testing is done with hypervariable DNA markers, nondetectable alleles should not be ignored. This work presents simple formulae needed with this consideration, to analyze paternity evaluation from DNA markers in cases where the mother of the disputed child is unavailable for testing. It is shown that even a modest frequency of nondetectable alleles (e.g., 2–5% per locus) may have a substantial impact on the paternity index when the child and/or the alleged father exhibits a single-banded DNA profile at a locus. Use of such formulae can generate a high probability of exclusion and a high paternity index when multiple independently segregating hypervariable DNA markers are used.     

Application of single-locus hypervariable region DNA probes to deficiency cases in paternity testing

Summary Seven DNA probes which recognize single-locus hypervariable region (HVR) were applied to a paternity test in which the putative father and his wife were deceased. Three legitimate children, an illegitimate child and her mother were available for analysis. The cumulative paternity index of the illegitimate child derived from 15 conventional blood group markers was 18.71 and from 7 DNA probes 92,572.08, that is, 4,948 times higher than the former. Thus the DNA analyses gave nearly conclusive evidence that the putative father was the biological father of the child. The application of highly discriminating polymorphisms of DNA which recognize single HVR loci is considered to be extremely informative in cases of disputed parentage.     

Gebrauch X-chromosomaler Marker in der forensischen Genetik

Apart from some exceptions typing of autosomal short tandem repeats is normally sufficient for kinship testing in the standard trio situation consisting of the mother, child and putative father. Nevertheless, there are some constellations, such as deficiency and incest cases, which require X-chromosomal typing. However, application is only possible in X-chromosomal inheritance lineages. X-chromosomal haplotyping is suitable for proving distant kinship, such as aunt/niece or first cousins. As male individuals only have one X chromosome the haplotype can be directly recognized by typing the markers and both haplotypes of female individuals often can be deduced from pedigree analysis. X-chromosomal testing can be effective in incest cases or to solve cases in which two alleged fathers are related. In forensic stain analysis X-chromosomal analyses should be utilized when a female component has to be identified in a mixture contaminated with male components. A series of ethical aspects have to be considered when X-chromosomal markers are investigated.     

荧光染色体原位杂交技术在产前诊断中的应用

目的 建立并优化荧光染色体原位杂交技术并评价其在胎儿21、18、13、X和Y染色体数目异常产前诊断中的临床应用价值.方法 常规穿刺取羊水或脐带血样本196例,经低渗、固定、制片、老化等,直接利用两组特异性探针(GLP 13/GLP 21和CSP18/CSP X/CSP Y)进行原位杂交,快速检测羊水或脐带血细胞中21、18、13、X和Y染色体的数目,并同时对样本进行经典的细胞培养和染色体核型分析.结果 以≥90％的细胞显示的荧光信号点数目作为染色体数目的判断标准,正常情况下GLP 13/GLP 21探针组显示2个绿色荧光点/2个红色荧光点,CSP18/CSP X/CSPY探针组显示2个蓝绿色荧光点/2个黄色荧光点(女性)或者2个蓝色荧光点/1个黄色荧光点/1个红色荧光点(男性).196例羊水或脐血均在72～96h内给出报告,检出21三体综合征7例、l8三体综合征2例、性染色体异常(47,XYY)1例,与1个月后报告的染色体核型分析结果一致.结论 荧光染色体原位杂交方法可用于快速产前诊断胎儿21、18、13、X、Y染色体数目异常,与常规的染色体核型分析技术结合,可快速准确地检测胎儿染色体的非整倍体异常.     

Concurrent copy number variations on chromosome 8 and 22 combined with mutation at FGA locus revealed in a parentage testing case

Copy number variations (CNVs) are one of the major sources of human genetic diversity and are associated with rare genomic disorders as well as complex traits and diseases. A copy number variation was observed at the D8S1179 locus during routine STR based parentage testing, in which the child exhibited three alleles, “13, 15, 16”, with the putative father a homozygous “15” and the mother homozygous “13”. In addition, in the same testing case, there was a one-step mutation at the STR locus FGA, in which the putative father was a “22, 24”, the mother was a “22, 25”, and the child was a “22, 23”. After further investigations by re-amplified with different primer sets, clone-based sequencing, karyotype analysis and whole-genome SNP analysis, the results showed that the child had the CNVs at chromosome 8q24.3 and 22q11.21. In conclusion, for parentage testing cases encountered with tri-allele patterns, more testings, such as cloning sequencing, karyotyping, or even whole genome analysis, as well as more appropriate statistical estimations might be conducted to further confirm or exclude the relationship.     

Assessing paternities with inconclusive STR results: The suitability of bi-allelic markers

In paternity testing the genetic profiles of the individuals are used to compare the relative likelihoods of the alleged father and the child being related as father/offspring against, usually, being unrelated.In the great majority of the cases, analyses with the widely used sets of short tandem repeat markers (STRs) provide powerful statistical evidence favouring one of the alternative hypotheses. Nevertheless, there are situations where the final statistical result is ambiguous, mostly because the alleged father shows incompatible genotypes at a few loci along with a very high paternity index in the remaining systems. In these cases, the possibility that the alleged father is actually a close relative of the real one (son, father or brother) can reasonably be raised.In such cases, when the statistical evidence obtained is considered as insufficient, the common practice is to extend the set of analysed markers. In this context, many authors have suggested that bi-allelic markers, such as single nucleotide (SNP) or insertion/deletion (Indel) polymorphisms, are markers of choice, as they are incomparably less prone to mutation than STRs.In this work we address the soundness of this claim and the consequences of this strategy, analyzing the a priori odds both for (a) expected number of Mendelian incompatibilities, and (b) expected values for the final likelihood ratios. Moreover, one hundred real pairs of second degree relatives, typed for two sets of markers: 15 STRs plus 38 Indels, were used to simulate paternity testing. Our data show that, for the number of markers commonly considered, the results from an extended battery of SNPs or Indels should be interpreted with caution when relatives are possibly involved.     

18FDG uptake associated with CT density on PET/CT in lungs with and without chronic interstitial lung diseases

Objective  The dependent-density of computed tomography (CT) images of positron emission tomography (PET)/CT is sometimes difficult to distinguish from chronic interstitial lung disease (ILD) when it accompanies increased ¹⁸F-fluorodeoxy-d-glucose (¹⁸FDG) uptake. Though the possible utility of ¹⁸FDG-PET for the diagnosis of active ILD has been reported, the clinical relevance of mild lung ¹⁸FDG uptake in ILD cases without signs and symptoms suggesting acute progression has not been described. This study aimed to test relationships between ¹⁸FDG uptake and lung density on CT using PET/CT in patients with normal lung as well as clinically stable chronic ILD. Methods  Thirty-six patients with normal lungs (controls) and 28 patients with chronic ILD (ILD cases) without acute exacerbation were retrospectively selected from ¹⁸FDG-PET/CT scans performed in examination of malignant neoplasms. Elliptical regions of interest (ROIs) were placed on the lung. The relationships between CT density and ¹⁸FDG uptake between the control and ILD cases were tested. Results  The CT density and ¹⁸FDG uptake had a linear correlation in both the controls and the ILD cases without a difference in their regression slopes, and they were overlapped between the controls and the ILD cases with higher mean values in the ILD cases. Conclusions  Lung ¹⁸FDG uptake was considered to reflect a gravity-dependent tissue density in the normal lung. Though the lung ¹⁸FDG uptake as well as the CT density tended to be higher in chronic ILD patients, it may be difficult to distinguish them in normal dependent regions from those related to chronic ILD in some cases.     

Investigation of paternity with alleged father deceased or missing: Analysis of success at the end of the report

In this work we present a retrospective study of 858 cases of paternity investigation performed in Rio Grande do Sul, Southern Brazil, from 2007 to 2012, where the alleged father was deceased or missing. These cases represent 3.3% (858/26187) of paternity tests performed in that period. Considering the analysis of 17 DNA short tandem repeat loci, we present here the proportion of cases with conclusive results according to the number of relatives of the unavailable alleged father investigated and their kinship. The results show 81.0% (695/858) of cases with conclusive results and their characteristics.     

放射性介入治疗中知情现状调查及其影响因素

目的:了解放射性介入治疗中患者对X射线危害性的知情现状及医生对患者的告知情况,并分析其影响因素.方法:随机抽取上海4家医院共60位接受放射性介入治疗的患者或家属,发放调查问卷,回收并分析结果.结果:55位(96％)患者表示其接受介入治疗前主治医生明确向其告知了X射线损伤的相关信息.接受问卷调查的所有患者均认为医生告知其X射线的危害性是非常有必要的.学历水平较高者及有从事医务工作亲友者在受诊前对X射线损伤知晓率明显高于学历水平低者或没有从事医务工作亲友者,(P =0.001).结论:各知识阶层及家庭状况不同的患者对X线放射性损伤的了解情况存在差异.放射性介入治疗中X射线危害性的知情同意实施力度尚可,但仍需加强,特别是对文化水平不高以及没有从事医疗工作亲友的患者.     

Chemoembolic Hepatopulmonary Shunt Reduction to Allow Safe Yttrium-90 Radioembolization Lobectomy of Hepatocellular Carcinoma

Yttrium-90 (⁹⁰Y) radioembolization represents an emerging transcatheter treatment option for the management of hepatocellular carcinoma (HCC). Elevation of the hepatopulmonary shunt fraction risks nontarget radiation to the lungs and may limit the use of ⁹⁰Y therapy in patients with locally advanced disease with vascular invasion, who often demonstrate increased shunting. We present two cases in which patients with HCC and portal vein invasion resulting in elevated hepatopulmonary shunt fractions underwent chemoembolic shunt closure to allow safe ⁹⁰Y radioembolization. Both patients demonstrated excellent tumor response and patient survival. On this basis, we propose a role for chemoembolic reduction of the lung shunt fraction before ⁹⁰Y radioembolization in patients with extensive tumor-related hepatopulmonary shunting.     

Demonstration of false inclusion risks of duo parentage analyses in the Turkish population in light of parentage acceptance criteria

In routine parentage tests, trio analyses (father-mother-child) are preferred. Under certain circumstances, laboratories may have to perform duo analysis (without mother/father). However, duo analyses increase the risk of false inclusions. This paper aimed to evaluate the false inclusion risks of duo analyses in the Turkish population from the point of forensic applications and the Turkish judicial system. Children from 400 previously analysed cases were compared separately with fathers and mothers of other cases by using a computer programme. From the total 345,006 comparisons, in 16 comparisons, no Short Tandem Repeat (STR) mismatch was observed at 15 STR loci between the child and an unrelated parent. In other words, duo tests provided a coincidental second mother or father to 16 children. In almost all of these cases, the probabilities of paternity estimation values are greater than Turkish Judicial System’s parentage acceptance limit, which is 99.73%. According to results, we suggested that trio cases should be performed as much as possible and the parentage acceptance limit, which is 99.73%, should be re-evaluated by a law maker’s commission to prevent false inclusion parentage cases in Turkey.     

Calculation of percentage of cases on file with an unnamed father in 100 one-man and 100 two-man cases (filiation cases) from South-West Germany in 1976–1981

Summary Applying the formula of Schulte-Mönting and Hummel to 100 one-man affairs (filiation cases) in South-West Germany between 1979 and 1981 gave a realistic prior probability of paternity of 0.837±0.0372. This means that in approximately 83.7% of all one-man affairs the man named by the mother to be the father of her child is indeed the father.For two-man affairs a realistic prior probability of paternity of 0.863±0.0369 was calculated on the basis of 100 two-man affairs in South-West Germany between 1976 and 1981. In other words, there is a probability of about 86.3% that a non-excludable man—irrespective of other factors—in a two-man affair is the real father of the child. In approximately 13.7% of two-man affairs neither the defendant nor the witness is the father, but a third unknown person. In about 85.7% of the two-man affairs in which a father of the child was named the defendant is in fact the father and in 14.3% the witness is the father.     

Erythrocytäre Enzympolymorphismen in der forensischen Serologie

Zusammenfassung Es wird berichtet über die erythrocytären Enzympolymorphismen: saure Erythrocytenphosphatase, Phosphoglucomutase, 6-Phosphogluconat-Dehydrogenase, Adenosindeaminase, Adenylatkinase. Die beobachteten Phä notypen einschließlich der seltenen Varianten werden beschrieben. Eine Beschreibung der physikochemischen Eigenschaften folgt. Die meisten der bisher mitgeteilten Genfrequenzen werden tabellarisch dargestellt. Eine tabellarisch zusammengefaßte Aufstellung der bisher publizierten Familiendaten erfolgt für jedes Enzym. Die Anwendbarkeit und der Sicherheitsgrad bei der Abstammungsbegutachtung werden diskutiert. Über die publizierten Nachweisgrenzen aus gelagerten Blutspuren und Blutproben wird ebenfalls berichtet.

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Summary It is reported on the use of five red cell enzyme polymorphisms in forensic serology. Acid Photophatase. Some electrophoretic methods are given, classifiable roughly into three categories of isozyme patterns. Available physico-chemical properties are reported. Recent data suggest that the two isozymes, produced by one allele are conformational isomers. Gene frequencies in european populations show certain north-to-south differences that sould be accomodated on, if the probability of the paternity has to be calculated. From the present literature 4151 mother/child pairs are summarized without exception of the postulated gene model. The constellation of exclusion child-homozygous, accused man—oppositely homozygous, should be reinvestigated by quantitative gene dosage measurements to exclude the existence of the P⁰ allele.Discrepant data are available on the literature about the use in identification cases of bloodstains and bloodsamples. These problems need further clarification by more sensitive procedures. Phosphoglucomutase. Electrophoretic methods and physicochemical properties are reported. Gene frequencies in several populations are given. Certain north-to-south differences between european populations should be taken into account. 4966 mother/child pairs have been summarized from the literature without genetic incompatibility. The existence of the PGM ₁ ⁰ allele should be considered too when an opinion is given on exclusion cases with opposite homozygosis. There is a good chance in bloodstain and blood sample identification cases to determine this enzyme after considerable time of storage. 6-Phosphogluconate-dehydrogenase. A designation with letters only is used for the different genes and Phenotypes. Methods for the electrophoretic separation and enzyme's physicochemical properties are given. Differences of gene frequencies between northern and southern european populations have to be considered in paternity proceedings. 933 mother/child pairs have been reported in the literature without any irregularities. As exclusion cases will occur mostly, when the child is heterozygous (AB) and the accused man homozygous (A), there is a high degree of reliability, when one has to give an opinion on this constellation. The identification in stored bloodstains is possible up to 4 weeks. Adenosine Deaminase. Methods of determination and the physico-chemical properties are described. It is pointed out to the rather quick changes of patterns that occur on storage. For gene frequencies in european populations there seems to be present a north-to-south trend. 1600 mother/child pairs have been published without exception of the mendelian rules. According to the PGD-system the normal exclusion cases should be judged to be reliable. The determination of this enzyme in bloodstains is possible after considerable time of storage. Adenylate Kinase. Some methods of determination and the properties of the enzyme are reported. Gene frequencies in most european populations are rather homogeneous. 1510 mother/child pairs are available on the literature. Normal exclusion cases (heterozygous child, homozygous man) should be judged to be reliable. Identification in stored blood samples and in stains is possible after long time storage.Some other red cell enzyme polymorphisms are shortly reported too.

     

Mathematical aspects of the paternity index I=X/Y,especially in relation to the chance of non-exclusion of non-fathers

Summary In a previous paper the author mentioned some aspects of the paternity index I (=X/Y): Among false triplets the frequency of those with I equal to or higher than an (observed) I value of I ^x is considerably lower than 1/I ^x; among false triplets the mean value of I is equal to 1, and among non-excluded non-fathers it is equal to the inverse of the chance of non-exclusion; among true triplets the mean value of 1/I (=i) is equal to the chance of non-exclusion of non-fathers. In a statistical material rather strong deviations from some of these expectations were observed.In the present paper further characteristics of the distribution of I values were taken into consideration, and especially those that should hold if lnI would fit in with a normal distribution. It was supposed that with the aid of such a distribution the deviations mentioned above could be recognized as chance variability. It appears, however, that neither the logarithms of the paternity index, nor those of the zygosity index of twins (chosen as an analogous model that is more easily analysable than the paternity index) are really normally distributed. This, in turn, makes that estimates of probability of paternity, based on such a supposition, are of doubtful reliability. Besides it is concluded that also for other reasons other estimates than Essen-Möller's W (or I or i), as probability of first type errors, lead in practice to conclusions that are equally subdue to a priori suppositions as are W values and may be, in fact, much more erroneous than those.Special attention is paid to the statistical analysis of paternity studies with more than one alleged father, and it is concluded that in such cases the general formula that may be considered to be equivalent with Essen-Möller's formula for one-man paternity cases, i.e., W=X/(X+Y) or I/(I+1), must be W ₁=I ₁/(I+n); W ₂=I ₂/(I+n) etc. and certainly not W ₁=I ₁/(I+1); W ₂=I ₂/(I+1) etc.Dedicated to Prof. Dr. Erik Essen-Möller on the occasion of his 80th birthday     

Paternity exclusion power: Comparative behaviour of autosomal and X-chromosomal markers in standard and deficient cases with inbreeding

In paternity testing the informativeness of genetic markers is traditionally measured through the probability of finding, in randomly chosen individuals, inconsistencies with parent to child Mendelian rules of transmission. This statistic, called power of exclusion (PE), paternal exclusion chance or probability, can be defined for duos (mother not typed) or trios (random false fathers are matched against mother/child pairs) and performed both for autosomal and X-chromosomal markers (restricted to paternity testing involving daughters). PE is an a priori statistic, in the sense of not depending on the individual's genetic data of a case, being dependent however on the estimates of genetic markers allele (or haplotype) frequencies.We have studied the behaviour of this statistic in situations where the randomness assumption is not met, because either (a) the alleged – and false – father is related to the true one, or (b) there is a non-negligible level of background relatedness in the population.For the first case, we derived general (autosomal and X-chromosomal) PE formulas for duos and trios for any genealogy linking alleged father and child, highlighting that the PE of each marker only depends on a single kinship parameter associated with their pedigree. In this case we also estimate a lower bound for the number of extra markers needed to be analysed to achieve the same global power as for unrelated individuals. In the second situation, we demonstrate that for realistic values of the coancestry coefficient the decrease in PE due to population inbreeding is very moderate even when duos are analysed.In this work, beyond the aforementioned issues, we also discuss the suitability of assuming the pedigree father–daughter for calculating the X-PE, since X-markers are not the tool of choice in laboratorial routine when the alleged father is available for testing. Indeed, X-markers are particularly useful in situations where the alleged father is not available for testing but experts are able to type the mother or a daughter of his. Such increase of power is due to the paternal genealogies: half- and full-sisters, and grandmother–granddaughter, having a non-null X-PE even when only duos are analysed in contrast to what happens for autosomes. Algebraic expressions for these cases are also presented.     

Paternity testing with VNTR DNA systems

Summary Paternity testing using DNA polymorphism of variable numbers of tandem repeat (VNTR) regions with restriction fragment length polymorphism (RFLP) was implemented. HinfI-digested DNA was separated by electrophoresis in agarose gels and hybridized with radiolabelled probes detecting the VNTR-systems D2S44 (YNH24), D5S43 (MS8), D7S21 (MS31), D7S22 (g3), and D12S11 (MS43a). The intra gel variability of 970 duplicate investigations on the same gel of DNA from 122 individuals showed no differences exceeding 1.25 mm between the positions of the corresponding DNA fragments. The comparison of 1,624 DNA fragments from 342 mother/child pairs showed only one difference above 1.25 mm which was interpreted as a mutation. Based on these observations, we decided to consider an intra gel difference above 1.25 mm between the non-maternal DNA fragment of the child and the nearest DNA fragment of the putative father as an exclusion in paternity testing. This matching criterion was used for the comparisons of 1,197 DNA fragment differences in 247 pairs of children and putative fathers who had not been excluded by conventional marker systems. In all of these cases, the migration differences between the DNA fragments of non-excluded men and the DNA fragments of the children were less than 1.25 mm except in 6 cases (0.5%). The man/child differences in all of 227 false trios exceeded 1.25 mm in 2 or more of the 5 VNTR systems investigated. Matching criteria for inter gel comparisons in paternity testing were established. The frequency distribution of Hinfl digested DNA fragments of the 5 VNTR systems in 650 unrelated Danes is presented and the raw data is available.     

Distribution of Likelihood Ratio in Relation to the Exclusion Probability

Summary The relation between the exclusion probability (E) and the paternity probability is derived by assuming the distributions of logarithm of paternity likelihood ratio, log (Y/X) for true fathers and unexcluded non-fathers as the normal distributions.Under this assumption the value log(l -E) is equal to the mean of the mean value for true fathers (a) and that for unexcluded non-fathers (b), i.e., log(l-E) = (a +b)/2. This relation holds quite well for the various actual distributions of log(Y/X) of father-child combinations and those of father-mother-child combinations using 14 blood group systems. Therefore, the derived relation is found to be a convenient way to deduce one of the three quantities (E, a, b) from the remaining two quantities in the actual distributions.