Do bilineal pedigrees represent a problem for linkage analysis? basic principles and simulation results for single-gene diseases with no heterogeneity

Some investigators have expressed concern--especially for psychiatric disorders--that bilineal pedigrees should not be included in linkage studies. This study compares the "informativeness" of bilineal and unilineal families for a homogeneous single-gene disorder. Three approaches were used: (1) simulation studies of three-generation pedigrees, (2) calculation of expected lod scores (ELODs) in nuclear families, and (3) calculation of Fisher's information number I(theta) in nuclear families. The simulation studies in (1) permitted a realistic comparison between bilineal datasets and purely unilineal ones. The calculations in nuclear families in (2) and (3) then made it possible to analyze the sources of information loss in bilineal families. Overall, in datasets of five three-generation pedigrees each, the drop in mean maximum lod score was approximately 50% from purely unilineal datasets to extremely bilineal ones. In less-extreme bilineal datasets, which are closer to most real data than the extremely bilineal ones, the drops in lod score were very small--less than 10% in some, and practically zero in others. The details will vary, depending on size and structure of the pedigree, genetic model, true value of the recombination fraction, and informativeness of the marker. However, these results imply that the information loss due to bilineality is not necessarily very great. The nuclear-family calculations showed that for phase-known matings there is relatively little information loss in bilineal families, but for phase-unknown matings there the loss is much greater. In conclusion, for single-gene disorders with no genetic heterogeneity, whereas bilineal families can be less informative than comparable unilineal families, they are not so much less informative that they should automatically be discarded from linkage datasets. The implications of bilineal pedigrees for linkage studies of heterogeneous disorders are also discussed.     

Adenoid cystic carcinoma: factors influencing survival.

We have reviewed our experience with 264 patients treated for adenoid cystic carcinoma of salivary origin. This study updates a previous report from our hospital and includes all patients treated during a 30 year period who were eligible for a minimum follow-up of 10 years. The tumor arose in minor salivary (mucous) glands in two thirds of the patients; half had received treatment elsewhere, and both sexes were equally represented. Actuarial survival curves and "cure" rates calculated by the direct method confirm that clinical staging provides a reliable prognostic guide. We are unable to demonstrate that the microscopic appearance of the tumor exerts a predictable effect on treatment results. Although some patients lived for many years after resection despite local recurrence and distant metastases, prolonged survival was unusual in patients with stage 3 lesions, particularly in those with sinus or submaxillary gland primaries. Based on the site of origin of the tumor and its clinical stage, it is now possible to select which patients with adenoid cystic carcinoma have the most ominous prognosis and perhaps plan a more appropriate operation. More importantly, these data may help focus on the subpopulation at greatest risk, which is vital to the design of any prospective study to assess the value of adjunctive irradiation and chemotherapy.     

Duodenal and jejunal atresia with agenesis of the dorsal mesentery: "apple peel" small bowel.

Two newborn infants with duodenal and jejunal atresia and agenesis of the dorsal mesentery represent our surgical experience with "apple peel" small bowel or "christmas tree" demormity. The first patient had the typical appearance of this condition. The postoperative course was complicated by hyperbilirubinemia, septicemia, and disseminated intravascular coagulation. The infant is in satisfactory condition 1.5 years after operation. The second patient had agenesis of the dorsal mesentery without spiraling of the bowel around its vascular stalk. The child died after 1 month, with complete absence of extrahepatic bile ducts as seen at a second laparotomy. Neither child had been subjected to gastrostomy.     

Evaluation of the results of external choledochoduodenostomy for retained, recurrent, or primary common duct stones.

Twenty-five patients were treated for retained, recurrent, or primary common duct stones by permanent drainage of the biliary tract with external choledochoduodenostomy. Twenty-one patients had common duct stones which became evident two to fifty years after the initial biliary tract procedure and which may represent stones formed in the common duct. Three recent patients had a clinical history of primary common duct stones, had stones which were soluble in chloroform-methanol solution, and had hepatic bile which was lithogenic as determined by evaluating the molar percentage of cholesterol, phospholipid, and bile salt in bile samples obtained at the time of choledochoduodenostomy. These data suggest that further stone formation is possible and that permanent bypass of the sphincter of Oddi is indicated to prevent recurrent bile duct obstruction. Long-term evaluation of the results of external choledochoduodenostomy indicates that the procedure is safe and effective in the prevention of recurrent biliary tract calculi.     

Prosthetic arteriovenous fistula for vascular access in hemodialysis.

Vascular access through subcutaneous prosthetic arteriovenous fistulas was studied in eighteen dogs. Dacron velour and woven Dacron grafts (6 mm diameter) were constructed across the lower abdomen between the common femoral artery and the opposite common femoral vein. In heparinized animals 197 percutaneous punctures were made with a "14 guage hemodialysis cannula at weekly intervals. Over a period of one and a half years there was no instance of infection. One of the fourteen Dacron velous and all four woven Dacron fistulas thrombosed. These data suggested the feasibility of achieving repetitive blood access through Dacron velour vascular prostheses. Nineteen Dacron velour fistula bypasses between the brachial artery and median basilic vein were performed in fifteen selected patients for a total dialysis period of ninety-six months. Failed standard subcutaneous fistulas or absence of suitable vessels in the upper extremity were indications for the primary procedure. Of three looped forearm fistulas, two thrombosed at twenty-two and two months. Complications among sixteen straight bypasses in the arm included two graft infections and one cannula tract infection. There were no instances of thrombosis in this group. The advantages of single needle dialysis in these high risk patients have been emphasized. Eleven grafts are presently functioning two to nine months postoperatively. Our preliminary results suggest that a Dacron velour fistula merits consideration as an alternative for vascular access in maintenance hemodialysis.     

The effects of noise in cardiac diffusion tensor imaging and the benefits of averaging complex data

There is growing interest in cardiac diffusion tensor imaging (cDTI), but, unlike other diffusion MRI applications, there has been little investigation of the effects of noise on the parameters typically derived. One method of mitigating noise floor effects when there are multiple image averages, as in cDTI, is to average the complex rather than the magnitude data, but the phase contains contributions from bulk motion, which must be removed first. The effects of noise on the mean diffusivity (MD), fractional anisotropy (FA), helical angle (HA) and absolute secondary eigenvector angle (E2A) were simulated with various diffusion weightings (b values). The effect of averaging complex versus magnitude images was investigated. In vivo cDTI was performed in 10 healthy subjects with b = 500, 1000, 1500 and 2000 s/mm². A technique for removing the motion‐induced component of the image phase present in vivo was implemented by subtracting a low‐resolution copy of the phase from the original images before averaging the complex images. MD, FA, E2A and the transmural gradient in HA were compared for un‐averaged, magnitude‐ and complex‐averaged reconstructions. Simulations demonstrated an over‐estimation of FA and MD at low b values and an under‐estimation at high b values. The transition is relatively signal‐to‐noise ratio (SNR) independent and occurs at a higher b value for FA (b = 1000–1250 s/mm²) than MD (b ≈ 250 s/mm²). E2A is under‐estimated at low and high b values with a transition at b ≈ 1000 s/mm², whereas the bias in HA is comparatively small. The under‐estimation of FA and MD at high b values is caused by noise floor effects, which can be mitigated by averaging the complex data. Understanding the parameters of interest and the effects of noise informs the selection of the optimal b values. When complex data are available, they should be used to maximise the benefit from the acquisition of multiple averages. The combination of complex data is also a valuable step towards segmented acquisitions. Copyright © 2016 John Wiley & Sons, Ltd.